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| United States Patent |
6,172,228
|
|
Kashima
, et al.
|
January 9, 2001
|
Process for producing piperazinesulfonamide derivatives and salts thereof
Abstract
A process for advantageously preparing a piperazinesulfonamide derivative
represented by the general formula (III):
##STR1##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group; each
of R.sup.3 and R.sup.4 is independently hydrogen atom, a straight or
branched chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl
group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon
atoms, or a phenyl group which may be substituted; and Y is an alkylene
group having 1 to 12 carbon atoms, and a salt thereof.
| Inventors:
|
Kashima; Kenichi (Fujiidera, JP);
Sakamoto; Yasuhiko (Habikino, JP);
Ohta; Yoichiro (Takatsuki, JP);
Kawanishi; Kenji (Osaka, JP);
Takemura; Shigetaka (Osaka, JP);
Takemura; Yasuko (Osaka, JP)
|
| Assignee:
|
Azwell Inc. (Osaka, JP)
|
| Appl. No.:
|
453223 |
| Filed:
|
December 3, 1999 |
Foreign Application Priority Data
| Current U.S. Class: |
544/360; 544/398 |
| Intern'l Class: |
C07D 401/06; C07D 241/04; C07D 295/023 |
| Field of Search: |
544/360,398
|
References Cited
U.S. Patent Documents
| 5478941 | Dec., 1995 | Cossement et al. | 544/383.
|
| 5716950 | Feb., 1998 | Kashima et al. | 514/218.
|
| Foreign Patent Documents |
| 0558245A1 | Sep., 1993 | EP.
| |
| 2225321 | May., 1990 | GB.
| |
| WO 9519345 | Jul., 1995 | WO.
| |
| 95 19345 | Jul., 1995 | WO.
| |
Other References
Synthesis, "A novel synthesis of the enantimers of an antihistamine drug by
piperazine formation from a primary amine," Opalka et al., 766-768, Jan.
1995.
Synthesis, "A Novel Synthesis of the Enantiomers of an Antihistamine Drug
by Piperazine Formation from a Primary Amine," Opalka et al., Jan. 27,
1995, pp. 766-768.
Patent Abstracts of Japan, 62153280 A, Jul. 8, 1987.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Liu; Hong
Attorney, Agent or Firm: Birch, Stewart, Kolasch & Birch, LLP
Parent Case Text
This application is a continuation-in-part application of PCT/JP98/02399,
filed May 29, 1998, the entire contents of which are incorporated herein
by reference.
Claims
What is claimed is:
1. A process for preparing a piperazinesulfonamide compound represented by
the formula (III):
##STR12##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group,
amino group, 2-pyridyl group, 3-pyridyl group and 4-pyridyl group; each of
R.sup.3 and R.sup.4 is independently hydrogen atom, a straight or branched
chain allyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having
1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a
phenyl group which may have as substituents on its phenyl ring 1 to 3
groups selected from the group consisting of an alkyl group having 1 to 4
carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom,
hydroxyl group, trifluoromethyl group, nitro group and amino group; and Y
is an alkylene group having 1 to 12 carbon atoms, comprising:
reacting a piperazine compound represented by the formula (I):
##STR13##
wherein R.sup.1 and R.sup.2 are as defined above, with a
halogenoalkylsulfonamide compound represented by the formula (II):
##STR14##
wherein R.sup.3, R.sup.4 and Y are as defined above; and X is chlorine
atom, bromine atom or iodine atom, in the presence of an organic base
selected from the group consisting of N-ethyldiiso-propylamine,
N-ethylmorpholine, triethylamine and 2,4,6-trimethylpyridine, and in the
absence of a solvent.
2. The process as claimed in claim 1, wherein the piperazinesulfonamide
compound represented by the formula (III) having optical activity is
prepared by using piperazine compound represented by the formula (I)
having optical activity.
3. The process as claimed in claim 1, wherein R.sup.1 is hydrogen atom, a
straight or branched chain alkyl group having 1 to 4 carbon atoms, an
alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxyl group,
trifluoromethyl group, nitro group or amino group.
4. The process as claimed in claim 1, wherein R.sup.1 is hydrogen atom or a
halogen atom.
5. The process as claimed in claim 1, wherein R.sup.1 is a halogen atom at
meta-position or para-position.
6. The process as claimed in claim 1, wherein R.sup.2 is a phenyl group
which may have as substituents one or two halogen atoms on its phenyl
ring, 2-pyridyl group or 4-pyridyl group.
7. The process as claimed in claim 1, wherein R.sup.2 is a phenyl group
which may have as a substituent one halogen atom on its phenyl ring,
2-pyridyl group or 4-pyridyl group.
8. The process as claimed in claim 1, wherein R.sup.2 is unsubstituted
phenyl group.
9. The process as claimed in claim 1, wherein each of R.sup.3 and R.sup.4
is independently hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon
atoms or a cycloalkyl group having 3 to 8 carbon atoms.
10. The process as claimed in claim 1, wherein each of R.sup.3 and R.sup.4
is independently hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon
atoms or a cycloalkyl group having 3 to 6 carbon atoms.
11. The process as claimed in claim 1, wherein each of R.sup.3 and R.sup.4
is independently a straight or branched chain alkyl group having 1 to 6
carbon atoms.
12. The process as claimed in claim 1, wherein R.sup.4 is hydrogen atom.
13. The process as claimed in claim 1, wherein R.sup.3 is a hydroxyalkyl
group having 1 to 4 carbon atoms, and R.sup.4 is hydrogen atom.
14. The process as claimed in claim 1, wherein R.sup.3 is a cycloalkyl
group having 3 to 6 carbon atoms, and R.sup.4 is hydrogen atom.
15. The process as claimed in claim 1, wherein the organic base is
N-ethyldiisopropylamine or triethylamine.
16. A process for preparing a pharmaceutically acceptable salt of a
piperazinesulfonamide compound represented by the formula (III):
##STR15##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
amino group, 2-pyridyl group, 3-pyridyl group and 4-pyridyl group; each of
R.sup.3 and R.sup.4 is independently hydrogen atom, a straight or branched
chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having
1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a
phenyl group which may have as substituents on its phenyl ring 1 to 3
groups selected from the group consisting of an alkyl group having 1 to 4
carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom,
hydroxyl group, trifluoromethyl group, nitro group and amino group; and Y
is an alkylene group having 1 to 12 carbon atoms, comprising the step of
preparing the piperazinesulfonamide compound represented by the formula
(III) by the process according to claim 1.
17. The process as claimed in claim 16, wherein the pharmaceutically
acceptable salt of the piperazine compound represented by the formula
(III) having optical activity is prepared by using a piperazine compound
represented by the formula (I) having optical activity.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing a
piperazinesulfonamide derivative and a pharmaceutically acceptable salt
thereof. More specifically, the present invention relates to a process for
preparing a piperazinesulfonamide derivative and a pharmaceutically
acceptable salt thereof which have excellent antiallergic activity and
thereby are useful as a medicament for preventing and treating diseases
such as bronchial asthma, allergic rhinitis, atopic dermatitis, urticaria
and the like.
2. Discussion of the Related Art
Conventionally, as processes for preparing a piperazinesulfonamide
derivative, there have been known, for instance, process A, process B and
process C which are described in WO95/19345 Pamphlet.
However, since the reaction processes of process A and process C are long,
and the yield of the piperazinesulfonamide derivative is low, it cannot be
said that these processes are industrially advantageous. In addition,
since process B requires a long period of time for completion of the
reaction, and the yield is not a satisfactory level, it cannot be said
that process B is industrially advantageous.
Therefore, recently, it has been required to develop a process capable of
industrially advantageously preparing a piperazinesulfonamide derivative
in a short period of time and at high yield.
In view of the above prior art, the present invention has been
accomplished, and an object of the present invention is to provide a
process for efficiently and industrially advantageously preparing a
piperazinesulfonamide derivative and a pharmaceutically acceptable salt
thereof.
These and other objects of the present invention will be apparent from the
following description.
SUMMARY OF THE INVENTION
In sum, the present invention pertains to:
(1) a process for preparing a piperazinesulfonamide derivative represented
by the general formula (III):
##STR2##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group; each
of R.sup.3 and R.sup.4 is independently hydrogen atom, a straight or
branched chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl
group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon
atoms, or a phenyl group which may have as substituents on its phenyl ring
1 to 3 groups selected from the group consisting of an alkyl group having
1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen
atom, hydroxyl group, trifluoromethyl group, nitro group and amino group;
and Y is an alkylene group having 1 to 12 carbon atoms,
characterized by reacting a piperazine derivative represented by the
general formula (I):
##STR3##
wherein R.sup.1 and R.sup.2 are as defined above, with a
halogenoalkylsulfonamide derivative represented by the general formula
(II):
##STR4##
wherein R.sup.3, R.sup.4 and Y are as defined above; and X is chlorine
atom, bromine atom or iodine atom, in the presence of an organic base and
in the absence of a solvent; and
(2) a process for preparing a pharmaceutically acceptable salt of a
piperazinesulfonamide derivative represented by the general formula (III):
##STR5##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group; each
of R.sup.3 and R.sup.4 is independently hydrogen atom, a straight or
branched chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl
group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon
atoms, or a phenyl group which may have as substituents on its phenyl ring
1 to 3 groups selected from the group consisting of an alkyl group having
1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen
atom, hydroxyl group, trifluoromethyl group, nitro group and amino group;
and Y is an alkylene group having 1 to 12 carbon atoms,
comprising the step of preparing the piperadinesulfonamide derivative
represented by the general formula (III) by the process according to item
(1) above.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the process for preparing a piperazinesulfonamide
derivative of the present invention is characterized by reacting a
piperazine derivative represented by the general formula (I):
##STR6##
wherein R.sup.1 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group; and R.sup.2 is a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group, with
a halogenoalkylsulfonamide derivative represented by the general formula
(II):
##STR7##
wherein each of R.sup.3 and R.sup.4 is independently hydrogen atom, a
straight or branched chain alkyl group having 1 to 6 carbon atoms, a
hydroxyalkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3
to 8 carbon atoms, or a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group; X is chlorine atom, bromine atom or iodine atom; and Y is
an alkylene group having 1 to 12 carbon atoms, in the presence of an
organic base and in the absence of a solvent.
In the piperazine derivative represented by the general formula (I),
R.sup.1 is hydrogen atom, a straight or branched chain alkyl group having
1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen
atom, hydroxyl group, trifluoromethyl group, nitro group or amino group;
and R.sup.2 is a phenyl group which may have as substituents on its phenyl
ring 1 to 3 groups selected from the group consisting of an alkyl group
having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group and amino
group, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group.
In R.sup.1, the straight or branched chain alkyl group having 1 to 6 carbon
atoms includes methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl
group, isopentyl group, sec-pentyl group, neopentyl group, tert-pentyl
group, n-hexyl group, isohexyl group, sec-hexyl group, neohexyl group and
tert-hexyl group.
The alkoxy group having 1 to 4 carbon atoms includes methoxy group, ethoxy
group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group,
sec-butoxy group, tert-butoxy group, and the like.
The halogen atom includes fluorine atom, chlorine atom, bromine atom and
iodine atom.
Among R.sup.1, hydrogen atom, a straight or branched chain alkyl group
having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group is preferable, and hydrogen atom or a halogen atom is more
preferable, and a halogen atom at meta-position or para-position is
particularly preferable.
In R.sup.2, as to the phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, the alkyl group having 1 to 4 carbon atoms includes
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
isobutyl group, sec-butyl group and tert-butyl group. The alkoxy group
having 1 to 4 carbon atoms includes methoxy group, ethoxy group, propoxy
group and butoxy group. The halogen atom includes fluorine atom, chlorine
atom, bromine atom and iodine atom.
R.sup.2 is preferably unsubstituted phenyl group, a phenyl group which may
have as substituents on its phenyl ring 1 or 2 halogen atoms, 2-pyridyl
group or 4-pyridyl group, more preferably unsubstituted phenyl group, a
phenyl group which may have as a substituent on its phenyl ring one
halogen atom, 2-pyridyl group or 4-pyridyl group, and particularly
preferably unsubstituted phenyl group.
In addition, among the piperazine derivatives represented by the general
formula (I), a compound in which R.sup.1 is hydrogen atom, a straight or
branched chain alkyl group having 1 to 4 carbon atoms, an alkoxy group
having 1 to 4 carbon atoms, a halogen atom, hydroxyl group,
trifluoromethyl group, nitro group or amino group; and R.sup.2 is a phenyl
group which may have as substituents on its phenyl ring 1 or 2 halogen
atoms, 2-pyridyl group or 4-pyridyl group is preferable, from the
viewpoint of obtaining a desired piperazinesulfonamide derivative
represented by the general formula (III), and in particular a compound in
which R.sup.1 is hydrogen atom or a halogen atom and R.sup.2 is
unsubstituted phenyl or a phenyl group which may have as a substituent on
its phenyl ring one halogen atom is more preferable.
Since the piperazine derivative represented by the general formula (I) has
one asymmetric carbon in some cases, there exists an optical active form
in the piperazine derivatives. In the piperazine derivative represented by
the general formula (I) having optical activity, R.sup.1 is hydrogen atom,
a straight or branched chain alkyl group having 1 to 6 carbon atoms, an
alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxyl group,
trifluoromethyl group, nitro group or amino group; and R.sup.2 is a phenyl
group which may have as substituents on its phenyl ring 1 to 3 groups
selected from the group consisting of an alkyl group having 1 to 4 carbon
atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom,
hydroxyl group, trifluoromethyl group, nitro group and amino group,
2-pyridyl group, 3-pyridyl group or 4-pyridyl group.
In R.sup.1, the straight or branched chain alkyl group having 1 to 6 carbon
atoms includes methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, Be
n-pentyl group, isopentyl group, sec-pentyl group, neopentyl group,
tert-pentyl group, n-hexyl group, isohexyl group, sec-hexyl group,
neohexyl group and tert-hexyl group.
The alkoxy group having 1 to 4 carbon atoms includes methoxy group, ethoxy
group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group,
sec-butoxy group, tert-butoxy group, and the like.
The halogen atom includes fluorine atom, chlorine atom, bromine atom and
iodine atom.
Among R.sup.1, hydrogen atom, a straight or branched chain alkyl group
having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a
halogen atom, hydroxyl group, trifluoromethyl group, nitro group or amino
group is preferable, and hydrogen atom or a halogen atom is more
preferable, and a halogen atom at meta-position or para-position is
particularly preferable.
In R.sup.2, as to the phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group, the alkyl group having 1 to 4 carbon atoms includes
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
isobutyl group, sec-butyl group and tert-butyl group. The alkoxy group
having 1 to 4 carbon atoms includes methoxy group, ethoxy group, propoxy
group and butoxy group. The halogen atom includes fluorine atom, chlorine
atom, bromine atom and iodine atom.
R.sup.2 is preferably unsubstituted phenyl group, phenyl group which may
have as substituents on its phenyl ring 1 or 2 halogen atoms, 2-pyridyl
group or 4-pyridyl group, more preferably unsubstituted phenyl group, a
phenyl group which may have as a substituent on its phenyl ring one
halogen atom, 2-pyridyl group or 4-pyridyl group, and particularly
preferably unsubstituted phenyl group.
In addition, among the piperazine derivatives represented by the general
formula (I) having optical activity, a compound in which R.sup.1 is
hydrogen atom, a straight or branched chain alkyl group having 1 to 4
carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom,
hydroxyl group, trifluoromethyl group, nitro group or amino group; and
R.sup.2 is a phenyl group which may have as substituents on its phenyl
ring 1 or 2 halogen atoms, 2-pyridyl group or 4-pyridyl group is
preferable, from the viewpoint of obtaining a desired
piperazinesulfonamide derivative represented by the general formula (III)
having pharmaceutically effective optical activity, and in particular a
compound in which R.sup.1 is hydrogen atom or a halogen atom and R.sup.2
is unsubstituted phenyl or a phenyl group which may have as a substituent
on its phenyl ring one halogen atom is more preferable.
Representative examples of the piperazine derivative represented by the
general formula (I) include, for instance,
1-[(3-chlorophenyl)phenylmethyl]piperazine,
1-[(4-chlorophenyl)phenylmethyl]piperazine,
1-[bis(4-chlorophenyl)methyl]piperazine,
1-[bis(3-chlorophenyl)methyl]piperazine,
1-[bis(4-fluorophenyl)methyl]piperazine,
1-[4-chlorophenyl-(2-pyridyl)methyl]piperazine,
1-[4-fluorophenyl-(2-pyridyl)methyl]piperazine,
diphenylmethylpiperazine, 1-[4-fluorophenyl(3-pyridyl)methyl]piperazine,
1-[4-chlorophenyl(4-pyridyl)methyl]piperazine,
1-[phenyl(4-pyridyl)methyl]piperazine,
1-[(4-methoxyphenyl)phenylmethyl]piperazine,
1-[( 2-fluorophenyl)phenylmethyl]piperazine,
1-[(4-methylphenyl)phenylmethyl]piperazine,
1-[(4-trifluoromethylphenyl)phenylmethyl]piperazine,
1-[(3-trifluoromethylphenyl)phenylmethyl]piperazine,
1-[(4-hydroxyphenyl)phenylmethyl]piperazine,
1-[(4-nitrophenyl)phenylmethyl]piperazine,
1-[(4-aminophenyl)phenylmethyl]piperazine,
1-[bis(2-chlorophenyl)methyl]piperazine,
1-[(3,4-dichlorophenyl)phenylmethyl]piperazine,
1-[(2-chorophenyl)phenylmethyl]piperazine,
(+)-1-[(3-chlorophenyl)phenylmethyl]piperazine,
(-)-1-[(3-chlorophenyl )phenylmethyl]piperazine,
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine,
(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine,
(+)-1-[(4-chlorophenyl-(2-pyridyl)methyl]piperazine,
(-)-1-[(4-chlorophenyl-(2-pyridyl)methyl]piperazine,
(+) -1-[4-fluorophenyl-(2-pyridyl )methyl]piperazine,
1(-)-1-[4-fluorophenyl-(2-pyridyl)methyl]piperazine,
(+)-1-[4-fluorophenyl-(3-pyridyl)methyl]piperazine,
(-)-1-[4-fluorophenyl-(3-pyridyl )methyl]piperazine,
(+)-1-[4-chlorophenyl-(4-pyridyl)methyl]piperazine,
(-)-1-[4-chlorophenyl-(4-pyridyl)methyl]piperazine,
(+)-1-[phenyl-(4-pyridyl)methyl]piperazine,
(-)-1-[phenyl-(4-pyridyl)ethyl]piperazine,
(+)-1-[(4-methoxyphenyl)phenylmethyl]piperazine,
(-)-1-[(4-methoxyphenyl)phenylmethyl]piperazine,
(+)-1-[(2-fluorophenyl)phenylmethyl]piperazine,
(-)-1-[(2-fluorophenyl)phenylmethyl]piperazine,
(+)-1-[(4-methylphenyl)phenylmethyl]piperazine,
(-)-1-[(4-methylphenyl)phenylmethyl]piperazine,
(+)-1-[(4-trifluoromethylphenyl)phenylmethyl]piperazine,
(-)-1-[(4-trifluoromethylphenyl)phenylmethyl]piperazine,
(+)-1-[(3-trifluoromethylphenyl)phenylmethyl]piperazine,
(-) -1-[(3-trifluoromethylphenyl)phenylmethyl]piperazine,
(+)-1-[(4-hydroxyphenyl)phenylmethyl]piperazine,
(-)-1-[(4-hydroxyphenyl)phenylmethyl]piperazine,
(+)-1-[(4-nitrophenyl)phenylmethyl]piperazine,
(-)-1-[(4-nitrophenyl)phenylmethyl]piperazine,
(+)-1-[(4-aminophenyl)phenylmethyl]piperazine,
1(-)-1-[(4-aminophenyl)phenylmethyl]piperazine,
(+)--[(3,4-dichlorophenyl)phenylmethyl]piperazine,
(-)-1-[(3,4-dichlorophenyl)phenylmethyl]piperazine,
(+)-1-[(2-chlorophenyl)phenylmethyl]piperazine,
(-)-1-[(2-chorophenyl )phenylmethyl]piperazine,
(+)-1-[(4-fluorophenyl)phenylmethyl)piperazine,
(-)-1-[(4-fluorophenyl)phenylmethyl]piperazine,
(+)-1-[(3-fluorophenyl)phenylmethyl]piperazine,
(-)-1-[(3-fluorophenyl)phenylmethyl]piperazine,
1-[(3-fluorophenyl)phenylmethyl]piperazine,
1-[(4-fluorophenyl)phenylmethyl]piperazine, and the like,
without intending to limit the present invention thereto.
The piperazine derivative represented by the general formula (I) can be
obtained by a method described, for instance, in Journal of Pharmaceutical
Science 67, 900, 1978, Japanese Patent Laid-Open No. 2816/1995, or the
like.
In the halogenoalkylsulfonamide derivative represented by the general
formula (II), each of R.sup.3 and R.sup.4 is independently hydrogen atom,
a straight or branched chain alkyl group having 1 to 6 carbon atoms, a
hydroxyalkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3
to 8 carbon atoms, or a phenyl group which may have as substituents on its
phenyl ring 1 to 3 groups selected from the group consisting of an alkyl
group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon
atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro group
and amino group; X is chlorine atom, bromine atom or iodine atom; and Y is
an alkylene group having 1 to 12 carbon atoms.
In each of R.sup.3 and R.sup.4, the straight or branched chain alkyl group
having 1 to 6 carbon atoms includes methyl group, ethyl group, n-propyl
group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group,
tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group,
neopentyl group, tert-pentyl group, n-hexyl group, isohexyl group,
sec-hexyl group, neohexyl group and tert-hexyl group. The hydroxyalkyl
group having 1 to 4 carbon atoms includes hydroxymethyl group,
hydroxyethyl group, hydroxypropyl group and hydroxybutyl group. The
cycloalkyl group having 3 to 8 carbon atoms includes cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group
and cyclooctyl group. In the phenyl group which may have as substituents
on its phenyl ring 1 to 3 groups selected from the group consisting of an
alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4
carbon atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro
group and amino group, the alkyl group having 1 to 4 carbon atoms includes
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
isobutyl group, sec-butyl group and tert-butyl group. The alkoxy group
having 1 to 4 carbon atoms includes methoxy group, ethoxy group, propoxy
group and butoxy group. The halogen atom includes fluorine atom, chlorine
atom, bromine atom and iodine atom.
Each of R and R.sup.4 is preferably hydrogen atom, a straight or branched
chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having
1 to 4 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms,
more preferably hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon
atoms, and a cycloalkyl group having 3 to 6 carbon atoms. In addition, it
is particularly preferable that each of these R.sup.3 and R.sup.4 is a
straight or branched chain alkyl group having 1 to 6 carbon atoms, or
R.sup.4 is hydrogen atom.
In the present invention, from the viewpoint of preparing a
piperazinesulfonamide derivative having excellent pharmacological
activity, a preferable combination of R.sup.3 and R.sup.4 is a combination
of R.sup.3 and R.sup.4 where R.sup.3 is a straight or branched chain alkyl
group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4
carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl
group which may have as substituents on its phenyl ring 1 to 3 groups
selected from the group consisting of hydroxyl group and an alkoxy group
having 1 to 4 carbon atoms and R.sup.4 is hydrogen atom; or a combination
of R.sup.3 and R.sup.4 where each of R.sup.3 and R.sup.4 is a straight or
branched chain alkyl group having 1 to 6 carbon atoms. More preferably,
the number of carbon atoms of the cycloalkyl group is 3 to 6, and the
substituents on its phenyl ring are three alkoxy groups having 1 to 4
carbon atoms. Among these combinations of R.sup.3 and R.sup.4, more
preferable are a combination where R.sup.3 is a hydroxyalkyl group having
1 to 4 carbon atoms, and R.sup.4 is hydrogen atom; a combination where
R.sup.3 is a cycloalkyl group having 3 to 6 carbon atoms, and R.sup.4 is
hydrogen atom; a combination where each of R.sup.3 and R.sup.4 is methyl
group; a combination where each of R.sup.3 and R.sup.4 is ethyl group; and
a combination where R.sup.3 is cyclopropyl group, cyclobutyl group or a
hydroxyalkyl group having 1 to 4 carbon atoms, and R.sup.4 is hydrogen
atom.
As described above, X is chlorine atom, bromine atom or iodine atom.
As described above, Y is an alkylene group having 1 to 12 carbon atoms,
preferably 5 to 12 carbon atoms, more preferably 5 to 8 carbon atoms. The
alkylene group may be a straight or branched chain.
Among the halogenoalkylsulfonamide derivatives represented by the general
formula (II), from the viewpoint of preparing a pharmacologically
effective piperazinesulfonamide derivative, particularly preferable ones
are a halogenoalkylsulfonamide derivative wherein each of R.sup.3 and
R.sup.4 is independently hydrogen atom, a straight or branched chain alkyl
group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4
carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms; X is chlorine
atom, bromine atom or iodine atom; and Y is an alkylene group having 1 to
12 carbon atoms.
Representative examples of the halogenoalkylsulfonamide derivative
represented by the general formula (II) include
6-chlorohexanesulfonamide,
N-cyclopropyl-6-chlorohexanesulfonamide,
N-cyclopropyl-6-bromohexanesulfonamide,
N-methyl-6-chlorohexanesulfonamide,
N,N-dimethyl-6-chlorohexanesulfonamide,
N-ethyl-6-chlorohexanesulfonamide,
N,N-diethyl-6-chlorohexanesulfonamide,
N-n-propyl-6-chlorohexanesulfonamide,
N-isopropyl-6-chlorohexanesulfonamide,
N-n-butyl-6-chlorohexanesulfonamide,
N-tert-butyl-6-chlorohexanesulfonamide,
N-n-pentyl-6-chlorohexanesul fonamide,
N-n-hexyl-6-chlorohexanesulfonamide,
N-cyclobutyl-6-chlorohexanesulfonamide,
N-cyclopentyl-6-chlorohexanesulfonamide,
N-cyclohexyl-6-chlorohexanesulfonamide,
N-cyclopropyl-5-bromopentanesul fonamide,
N-cyclopropyl-6-bromohexanesulfonamide,
N-cyclopropyl-7-bromoheptanesulfonamide,
N-cyclopropyl-8-bromooctanesulfonamide,
N-cyclopropyl-6-lodohexanesulfonamide,
N-cyclopropyl-9-chlorononanesulfonamide,
N-cyclopropyl-10-bromodecanesulfonamide,
N-cyclopropyl-11-bromoundecanesulfonamide,
N-cyclopropyl-12-bromododecanesulfonamide,
N-(2-hydroxyethyl)bromomethanesulfonamide,
N-(2-hydroxyethyl)-2-chloroethanesulfonamide,
N-(2-hydroxyethyl)-3-chloropropanesulfonamide,
N-(2-hydroxyethyl)-4-chlorobutanesulfonamide,
N-(2-hydroxyethyl)-5-chloropentanesulfonamide,
N-(2-hydroxyethyl)-6-chlorohexanesulfonamide,
N-(2-hydroxyethyl)-7-chloroheptanesulfonamide,
N-(2-hydroxyethyl)-8-chlorooctanesulfonamide,
N-(2-hydroxyethyl)-9-chlorononanesulfonamide,
N-(2-hydroxyethyl)-10-bromodecanesulfonamide,
N-(2-hydroxyethyl)11brmoundecanesulfonamide,
N-(2-hydroxyethyl)-12-bromododecanesulfonamide,
N-(3-hydroxypropyl )-5-chloropentanesulfonamide,
N-(4-hydroxybutyl)-5-chloropentanesulfonamide,
N-(3-hydroxypropyl)-6-chlorohexanesulfonamide,
N,N-(4-hydroxybutyl)-6-chlorohexanesulfonamide,
N,N-dimethylchloromethanesulfonamide,
N,N-dimethyl-2-chloroethanesulfonamide,
N,N-dimethyl-3-chloropropanesulfonamnide,
N,N-dimnethyl-4-chlorobutanesulfonamide,
N,N-dimethyl-5-chloropentanesulfonamide,
N,N-dimethyl-7-chloroheptanesulfonamiide,
N,N-dimethyl-8-chlorooctanesulfonamide,
N,N-dimethyl-9-chlorononanesulfonamide,
N,N-dimethyl-10-bromodecanesulfonamide,
N,N-dimethyl-11-bromoundecanesulfonamide,
N,N-dimethyl-12-bromododecanesulfonamide,
N,N-diethyl-5-chloropentanesulfonamide,
N,N-di-n-propyl-5-chloropentanesulfonamide,
N,N-di-n-butyl-5-chloropentanesulfonamide,
N,N-di-n-propyl-6-chlorohexanesulfonamide,
N,N-di-n-butyl-6-chlorohexanesulfonamide,
N-n-butyl-N-methyl-5-chloropentanesulfonamide,
N-n-butyl-N-methyl-6-chlorohexanesulfonamide,
and the like, but the present invention is by no means limited to these
compounds.
In the process for preparing the halogenoalkylsulfonamide derivative
represented by the general formula (II), a process for preparing a
halogenoalkylsulfonamide derivative wherein each of R.sup.3 and R.sup.4 is
hydrogen atom in the general formula (II) is different from that for
preparing a halogenoalkylsulfonamide derivative wherein R.sup.3 and
R.sup.4 are not simultaneously hydrogen atoms in the general formula (II).
The halogenoalkylsulfonamide derivative wherein each of R.sup.3 and R.sup.4
is hydrogen atom can be prepared, for instance, by a process disclosed in
The Journal of Organic Chemistry 52, 2162, 1987, or the like.
In addition, in the processes for preparing a halogenoalkylsulfonamide
derivative wherein R.sup.3 and R.sup.4 are not simultaneously hydrogen
atoms, a process for preparing a halogenoalkylsulfonamide derivative
represented by the general formula (IIa):
##STR8##
wherein R.sup.5 is hydrogen atom, a straight or branched chain alkyl group
having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon
atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group
which may have as substituents on its phenyl ring 1 to 3 groups selected
from the group consisting of an alkyl group having 1 to 4 carbon atoms, an
alkoxy group having 1 to 4 carbon atoms, a halogen atom, hydroxyl group,
trifluoromethyl group, nitro group and amino group; R.sup.6 is a straight
or branched chain alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl
group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon
atoms, or a phenyl group which may have as substituents on its phenyl ring
1 to 3 groups selected from the group consisting of an alkyl group having
1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen
atom, hydroxyl group, trifluoromethyl group, nitro group and amino group;
X.sup.1 is chlorine atom or bromine atom; and Y is the same as Y in the
general formula (II),
which is a compound wherein X is chlorine atom or bromine atom in the
general formula (II), is different from that for preparing a
halogenoalkylsulfonamide derivative represented by the general formula
(IIb):
##STR9##
wherein R.sup.5, R.sup.6 and Y are as defined above, which is a compound
wherein X is iodine atom in the general formula (II).
First, a process for preparing a halogenoalkylsulfonamide derivative
represented by the general formula (IIa) will be described.
The halogenoalkylsulfonamide derivative represented by the general formula
(IIa) can be obtained by reacting a halogenoalkylsulfonyl chloride
represented by the general formula (IV):
X.sup.1 --Y--So.sub.2 Cl (IV)
wherein X.sup.1 and Y are as defined above, with an amine represented by
the general formula (V):
##STR10##
wherein R.sup.5 and R.sup.6 are as defined above, in the presence or
absence of a base in a solvent or without a solvent.
As the halogenoalkylsulfonyl chloride represented by the general formula
(IV), there can be cited a halogenoalkylsulfonyl chloride represented by
the general formula (IVa):
Br--Y--SO.sub.2 Cl (IVa)
wherein Y is as defined above; and a halogenoalkylsulfonyl chloride
represented by the general formula (IVb):
Cl--Y--SO.sub.2 Cl (IVb)
wherein Y is as defined above.
In the general formula (IVa), Y is preferably an alkylene group having 5 to
12 carbon atoms.
The halogenoalkylsulfonyl chloride represented by the general formula (IVa)
is concretely a bromoalkylsulfonyl chloride.
Representative examples of the halogenoalkylsulfonyl chloride represented
by the general formula (IVa) include 5-bromopentanesulfonyl chloride,
6-bromohexanesulfonyl chloride, 7-bromoheptanesulfonyl chloride,
8-bromooctanesulfonyl chloride, 2-bromohexanesulfonyl chloride,
3-bromohexanesulfonyl chloride, 5-bromohexanesulfonyl chloride,
bromomethylenesulfonyl chloride, 2-bromoethanesulfonyl chloride,
3-bromopropanesulfonyl chloride, 4-bromobutanesulfonyl chloride,
9-bromononanesulfonyl chloride, 10-bromodecanesulfonyl chloride,
11-bromoundecanesulfonyl chloride and 12-bromododecanesulfonyl chloride.
The process for preparing the halogenoalkylsulfonyl chloride represented by
the general formula (IVa) will be described in detail in a later section.
The halogenoalkylsulfonyl chloride represented by the general formula (IVb)
is concretely a chloroalkylsulfonyl chloride.
Representative examples of the halogenoalkylsulfonyl chloride represented
by the general formula (IVb) include 5-chloropentanesulfonyl chloride,
6-chlorohexanesulfonyl chloride, 7-chloroheptanesulfonyl chloride,
8-chlorooctanesulfonyl chloride, 2-chlorohexanesulfonyl chloride,
3-chlorohexanesulfonyl chloride, 5-chlorohexanesulfonyl chloride,
chloromethanesulfonyl chloride, 2-chloroethanesulfonyl chloride,
3-chloropropanesulfonyl chloride, 4-chlorobutanesulfonyl chloride,
9-chlorononanesulfonyl chloride, 10-chlorodecanesulfonyl chloride,
11-chloroundecanesulfonyl chloride and 12-chlorododecanesulfonyl chloride.
In the amine represented by the general formula (V), R.sup.5 is hydrogen
atom, a straight or branched chain alkyl group having 1 to 6 carbon atoms,
a hydroxyalkyl group having 1 to 4 carbon atoms, a cycloalkyl group having
3 to 8 carbon atoms, or a phenyl group which may have as substituents on
its phenyl ring 1 to 3 groups selected from the group consisting of an
alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4
carbon atoms, a halogen atom, hydroxyl group, trifluoromethyl group, nitro
group and amino group; and R.sup.6 is a straight or branched chain alkyl
group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4
carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl
group which may have as substituents on its phenyl ring 1 to 3 groups
selected from the group consisting of an alkyl group having 1 to 6 carbon
atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom,
hydroxyl group, trifluoromethyl group, nitro group and amino group.
Among the amines represented by the general formula (V), from the viewpoint
of obtaining a desired halogenoalkylsulfonamide derivative represented by
the general formula (II), preferable ones are an amine wherein R.sup.5 is
hydrogen atom, and R.sup.6 is a straight or branched chain alkyl group
having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon
atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a phenyl group
which may have as substituents on its phenyl ring 1 to 3 groups selected
from the group consisting of hydroxyl group and an alkoxy group having 1
to 4 carbon atoms; and an amine wherein each of R.sup.5 and R.sup.6 is an
alkyl group having 1 to 4 carbon atoms. The number of carbon atoms of the
cycloalkyl group is more preferably 3 to 6, and the substituents on the
phenyl ring are more preferably three alkoxy groups having 1 to 4 carbon
atoms.
As representative examples of the amine represented by the general formula
(V), preferable ones are primary amines such as methylamine, ethylamine,
n-propylamine, isopropylamine, n-butylamine, isobutylamine,
sec-butylamine, tert-butylamine, n-pentylamine, isopentylamine,
sec-pentylamine, neopentylamine, tert-pentylamine, n-hexylamine,
isohexylamine, sec-hexylamine, neohexylamine, tert-hexylamine,
cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine,
hydroxymethylamine, hydroxyethylamine, hydroxypropylamine,
hydroxybutylamine and aniline; and secondary amines such as dimethylamine,
diethylamine, dipropylamine, dibutylamine and butylmethylamine. More
preferable ones are cyclopropylamine, cyclobutylamine, cyclopentylamine,
cyclohexylamine, hydroxyethylamine, hydroxypropylamine, hydroxybutylamine,
dimethylamine and diethylamine. Still more preferable ones are
cyclopropylamine, cyclobutylamine, hydroxyethylamine, hydroxypropylamine,
dimethylamine and diethylamine. Particularly preferable ones are
cyclopropylamine, hydroxyethylamine, hydroxypropylamine, dimethylamine and
diethylamine.
As described above, the halogenoalkylsulfonamide derivative represented by
the general formula (IIa) can be obtained by reacting a
halogenoalkylsulfonyl chloride represented by the general formula (IV)
with an amine represented by the general formula (V) in the presence or
absence of a base in a solvent or without a solvent.
It is preferable that the amount of the amine represented by the general
formula (V) is generally 2 to 4 mol per one mol of the
halogenoalkylsulfonyl chloride when the reaction is carried out in the
absence of an inorganic base, and that the amount of the amine is 1 to 3
mol per one mol of the halogenoalkylsulfonyl chloride when the reaction is
carried out in the presence of an inorganic base.
More strictly, when the reaction is carried out in the absence of an
inorganic base, the amount of the amine differs depending upon the kinds
of the amines. When the amine has one hydroxyalkyl group, it is desired
that the amount of the amine is 2 to 3.3 mol per one mol of the
halogenoalkylsulfonyl chloride. When the amine has two hydroxyalkyl
groups, it is desired that the amount of the amine is 2 to 4 mol per one
mol of the halogenoalkylsulfonyl chloride. In addition, when the amine has
no hydroxyalkyl group, it is desired that the amount of the amine is 2 to
2.2 mol per one mol of the halogenoalkylsulfonyl chloride.
When the reaction is carried out in the presence of an inorganic base, the
inorganic base includes, for instance, alkali metal hydroxides such as
lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium
hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,
potassium carbonate, and the like. Among them, alkali metal hydroxides
such as lithium hydroxide, sodium hydroxide and potassium hydroxide are
preferable.
It is desired that the amount of the inorganic base is not less than one
mol per one mol of the halogenoalkylsulfonyl chloride, from the viewpoint
of sufficient reduction of the amount of the amine, and that the amount of
the inorganic base is at most 1.5 mol, preferably at most 1.2 mol, from
the viewpoint of avoidance of the influence of hydrolysis.
When the inorganic base is used in the above amount, the amount of the
amine differs depending upon the kinds of the amines. When the amine has
one hydroxyalkyl group, it is desired that the amount of the amine is 1 to
1.5 mol per one mol of the halogenoalkylsulfonyl chloride. When the amine
has two hydroxyalkyl groups, it is desired that the amount of the amine is
1 to 3 mol per one mol of the halogenoalkylsulfonyl chloride. In addition,
when the amine has no hydroxyalkyl group, it is desired that the amount of
the amine is 1 to 1.2 mol per one mol of the halogenoalkylsulfonyl
chloride.
In the present invention, in the course of reaction, when the reaction is
carried out in the presence of the inorganic base as described above,
there is an advantage that the amount of the relatively expensive amine
represented by the general formula (V) can be reduced. Furthermore, since
the inorganic base is used, the resulting product can be easily separated
from the inorganic base after the conclusion of the reaction. Accordingly,
there is an advantage that complicated procedures are not required as in
the case where an organic base is used.
In the present invention, an organic base, such as pyridine, triethylamine,
diisobutylethylamine, N-ethyldiisopropylamine,
4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]-7-undecene or
1,4-diazabicyclo[2,2,2]octane, may be contained within the scope which
would not hinder the object of the present invention.
In the course of reaction, a solvent can be used. The solvent may be any
one as long as the reaction is not hindered. Representative examples of
the solvent include, for instance, diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform,
benzene, toluene, xylene, acetonitrile, acetone, methyl ethyl ketone,
ethyl acetate, hydrous solvents thereof, water, and the like. Among them,
from the viewpoint of industrial productivity, water can be favorably
used.
When the reaction is carried out in the absence of the inorganic base, the
halogenoalkylsulfonyl chloride can be reacted with the amine represented
by the general formula (V), for instance, by adding the
halogenoalkylsulfonyl chloride dropwise with stirring to the amine
dissolved in a solvent or to the amine without a solvent, or by adding
dropwise the amine with stirring under ice-cooling to the
halogenoalkylsulfonyl chloride dissolved in a solvent or to the
halogenoalkylsulfonyl chloride without a solvent. Alternatively, when the
reaction is carried out in the presence of the inorganic base, the
reaction may be carried out, for instance, by mixing the
halogenoalkylsulfonyl chloride with a solvent, adding thereto an inorganic
base under ice-cooling, and thereafter adding thereto the amine dropwise
with stirring, or by mixing the amine with a solvent, adding thereto the
base under ice-cooling, and thereafter adding thereto the
halogenoalkylsulfonyl chloride dropwise with stirring.
The atmosphere in the course of reaction is not limited to specified ones,
and it may be air or an inert gas atmosphere such as nitrogen gas. The
temperature inside the reaction system may be usually a temperature
ranging from 0.degree. C. to the boiling point of the solvent.
The conclusion of reaction can be regarded as a point at which the starting
materials disappeared when observed, for instance, by thin layer
chromatography.
After the conclusion of reaction, the resulting reaction mixture is washed
with, for instance, water, brine, or the like, and dried over, for
instance, anhydrous magnesium sulfate, or the like, and the filtrate is
concentrated in vacuo, to give a crude product. The
halogenoalkylsulfonamide derivative represented by the general formula
(IIa) can be obtained by purifying the crude product by means of, for
instance, silica gel column chromatography, recrystallization, or the
like.
When water is used as a solvent, the reaction mixture obtained after the
conclusion of reaction is extracted with, for instance, diethyl ether,
chloroform, ethyl acetate, or the like, and thereafter the same procedures
as above can be carried out.
Next, the process for preparing the halogenoalkylsulfonamide derivative
represented by the general formula (IIb) will be described.
The halogenoalkylsulfonamide derivative represented by the general formula
(IIb) can be obtained by reacting the halogenoalkylsulfonamide derivative
represented by the general formula (IIa) with sodium iodide.
In the course of reaction, a solvent can be used. As the solvent, any ones
can be used as long as the reaction is not hindered. There can be cited,
for instance, methyl ethyl ketone, acetone, and the like.
The halogenoalkylsulfonamide derivative represented by the general formula
(IIa) is dissolved in a solvent, and thereafter sodium iodide is added.
It is desired that the amount of sodium iodide is usually 1 to 3 mol,
preferably about 2 mol, per one mol of the halogenoalkylsulfonamide
derivative represented by the general formula (IIa).
After sodium iodide is added and dissolved therein, the resulting solution
is heated to a temperature of room temperature to the boiling point of the
solvent.
The heating time is not limited to specified ones, and heating can be
carried out until the conclusion of the reaction.
The conclusion of the reaction can be regarded as a point at which the
starting materials disappeared when observed, for instance, by thin layer
chromatography.
After the conclusion of the reaction, the resulting reaction mixture is
washed with, for instance, water, brine, and the like, and dried over, for
instance, anhydrous magnesium sulfate, or the like, and thereafter the
filtrate is concentrated in vacuo, to give a crude product. The
halogenoalkylsulfonamide derivative represented by the general formula
(IIb) can be obtained by purifying the crude product by means of, for
instance, silica gel column chromatography, recrystallization, or the
like.
Next, the process for preparing the halogenoalkylsulfonyl chloride
represented by the general formula (IVa) will be described.
The halogenoalkylsulfonyl chloride represented by the general formula (IVa)
can be obtained by reacting a sodium bromoalkylsulfonate represented by
the general formula (VI):
Br--Y--SO.sub.3 Na (VI)
wherein Y is as defined above, with a chlorinating agent.
Examples of the sodium bromoalkylsulfonate represented by the general
formula (VI) include sodium 5-bromopentanesulfonate, sodium
6-bromohexanesulfonate, sodium 7-bromoheptanesulfonate, sodium
8-bromooctanesulfonate, sodium 2-bromohexanesulfonate, sodium
3-bromohexanesulfonate, sodium 5-bromohexanesulfonate, sodium
bromomethanesulfonate, sodium 2-bromoethanesulfonate, sodium
3-bromopropanesulfonate, sodium 4-bromobutanesulfonate, sodium
9-bromononanesulfonate, sodium 10-bromodecanesulfonate, sodium
11-bromoundecanesulfonate and sodium 12-bromododecanesulfonate.
The sodium bromoalkylsulfonate represented by the general formula (VI) can
be obtained by known methods (Org. Synth., Coll. Vol. II, 558; WO95/19345
Pamphlet).
As the chlorinating agent used in the course of reaction, there can be
cited, for instance, phosphorus pentachloride, phosphorus trichloride,
phosphorus oxychloride, chlorosulfonic acid, sulfuryl chloride, thionyl
chloride, phosgene, oxalyl chloride, and the like.
When the sodium bromoalkylsulfonate represented by the general formula (VI)
is reacted with the chlorinating agent, a catalyst can be used.
As the catalyst, there can be cited, for instance N,N-dimethylformamide, or
the like.
In the course of reaction, the solution may be heated to room temperature
to 150.degree. C. or so. The heating time is not limited to specified
ones, and it may be a period until which the reaction is finished.
After the conclusion of reaction, the resulting reaction solution is washed
with, for instance, water, brine and the like, dried over, for instance,
calcium chloride or the like, and thereafter the filtrate is concentrated
in vacuo, to give the halogenoalkylsulfonyl chloride represented by the
general formula (IVa).
As described above, the piperazinesulfonamide derivative represented by the
general formula (III) can be obtained by reacting the piperazine
derivative represented by the general formula (I) with the
halogenoalkylsulfonamide derivative represented by the general formula
(II) in the presence of an organic base and in the absence of a solvent.
In the present invention, one of the features of the present invention
resides in that the piperazine derivative represented by the general
formula (I) is reacted with the halogenoalkylsulfonamide derivative
represented by the general formula (II) when the organic base is used
without a solvent. The desired piperazinesulfonamide derivative
represented by the general formula (III) can be prepared within a
surprisingly remarkably shortened reaction time and at high yield as
compared with the case where a solvent is used. In the present invention,
although some of the organic bases themselves simultaneously act as a
solvent, the term "in the absence of a solvent" described in the present
specification means that a solvent, such as water or an organic solvent,
which has been used in a general meaning, is not used, separately from the
organic base.
The organic base includes, for instance, pyridine, 2,4,6-trimethylpyridine,
triethylamine, diisobutylethylamine, N-ethyldiisopropylamine,
4-N,N-dimethylaminopyridine, N-ethylmorpholine,
1,8-diazabicyclo[5,4,0]-7-undecene, 1,4-diazabicyclo[2,2,2]octane, and the
like. These organic bases can be used alone or in admixture of two or more
kinds. Among these organic bases, N-ethyldiisopropylamine,
N-ethylmorpholine, triethylamine and 2,4,6-trimethylpyridine are
preferable, and N-ethyldiisopropylamine and triethylamine are more
preferable.
The amount of the organic base is preferably at least one mol per one mol
of the piperazine derivative represented by the general formula (I) in
order to obtain the desired product in a short period of time and at high
yield.
It is desired that the amount of the halogenoalkylsulfonamide derivative
represented by the general formula (II) is at least one mol, preferably 1
to 1.2 mol, per one mol of the piperazine derivative represented by the
general formula (I).
The reaction can be carried out by, for instance, refluxing the piperazine
derivative represented by the general formula (I) and the
halogenoalkylsulfonamide derivative represented by the general formula
(II) in the presence of the organic base.
The atmosphere in the course of reaction is not limited to specified ones,
and it may be air or an inert gas atmosphere, for instance, nitrogen gas.
The temperature in the reaction system may be usually within the range of
room temperature to a boiling point of the organic base used or so. The
reaction time differs depending on the reaction conditions, and it is
desired that the reaction time is usually 0.5 to 8.0 hours or so,
preferably 2 to 6 hours so that the reaction time can be remarkably
shortened as compared with the case where the solvent is used as described
above.
The conclusion of the reaction can be regarded as a point at which the
starting materials disappeared when observed, for instance, by thin layer
chromatography.
After the conclusion of the reaction, a crude product can be obtained by,
for instance, concentrating the resulting reaction mixture in vacuo,
adding water to the concentrate, extracting the mixture with chloroform,
washing the chloroform layer with water, drying over anhydrous magnesium
sulfate, and thereafter removing the solvent by evaporation in vacuo. The
piperazinesulfonamide derivative represented by the general formula (III):
##STR11##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Y are as defined above, can
be obtained by purifying the crude product by means of, for instance,
silica gel column chromatography, recrystallization, or the like.
According to the process of the present invention, the
piperazinesulfonamide derivative represented by the general formula (III)
can be industrially advantageously obtained in a short period of time and
at high yield.
Since some of the piperazinesulfonamide derivatives represented by the
general formula (III) have one asymmetric carbon atom, its optical isomer
exists therein. The present invention encompasses these steric isomers and
mixtures thereof.
In addition, the piperazinesulfonamide derivative represented by the
general formula (III) can be further formed into a salt by a conventional
method. The pharmaceutically acceptable salts include acid addition salts
and alkali addition salts. The acid addition salt includes, for instance,
inorganic acid salts such as hydrochloric acid salts, hydrobromic acid
salts, hydroiodic acid salts, sulfuric acid salts, nitric acid salts and
phosphoric acid salts; and organic acid salts such as acetic acid salts,
oxalic acid salts, maleic acid salts, fumaric acid salts, lactic acid
salts, malic acid salts, citric acid salts, tartaric acid salts,
methanesulfonic acid salts, ethanesulfonic acid salts and benzenesulfonic
acid salts. The alkali addition salt includes, for instance, salts of
alkali metal or alkaline earth metals such as sodium, potassium and
calcium, ammonium salts, or salts of organic bases such as methylamine,
ethylamine, dimethylamine, triethylamine, ethanolamine and piperidine.
EXAMPLES
Next, the present invention will be described in further detail on the
basis of the working examples, without intending to limit the scope of the
present invention only to these examples.
Preparation Example 1
Preparation of N-Cyclopropyl-6-chlorohexanesulfonamide
1 M-Aqueous sodium hydroxide (3.0 ml, 3.0 mmol) was added to a liquid
mixture of 6-chlorohexanesulfonyl chloride (657 mg, 3.0 mmol) synthesized
referring to the literatures of Bull. Soc. Chim. Belges., 74, 21 (1965)
and J. Org. Chem., 52, 2162 (1987) and water (9 ml) under ice-cooling.
Cyclopropylamine (206 mg, 3.6 mmol) was added dropwise thereto with
stirring. Thereafter, the mixture was stirred at the same temperature for
1.5 hours. The mixture was diluted with diethyl ether (30 ml), and an
organic layer was collected. The extract was washed with water and brine,
and thereafter dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by evaporation in vacuo. The crude
product was purified by column chromatography on silica gel with
chloroform, to give N-cyclopropyl-6-chlorohexanesulfonamide (588 mg) as
colorless crystals.
(1) Melting Point: 38.degree.-39.degree. C. (diethyl ether)
(2) IR vmax (KBr) cm.sup.-1 : 3267 (NH), 1317, 1135 (SO.sub.2)
(3) Mass Spectroscopy (C.sub.9 H.sub.18 ClNO.sub.2 S) EI: m/z 239 [M].sup.+
(4) EI-HRMS (C.sub.9 H.sub.18 ClNO.sub.2 S)
Calculated: 239.0745, Found: 239.0746
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.64-0.78 (4H, m, CHCH.sub.2 x2),
1.43-1.58 (4H, m, ClCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2), 1.72-1.89 (4H,
m, ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.54-2.61 (1H, m, CH),
3.06-3.11 (2H, m, SCH.sub.2), 3.55 (2H, t, J=6.5 Hz, ClCH.sub.2), 4.79
(1H, brs, NH)
(6) Elemental Analysis (C.sub.9 H.sub.18 ClNO.sub.2 S)
Calculated: C, 45.08; H, 7.57; N, 5.84
Found: C, 44.82; H, 7.50; N, 5.88
Preparation Example 2
Preparation of 6-Bromohexanesulfonyl Chloride
Thionyl chloride (10.3 ml, 140.4 mmol) and N,N-dimethylformamide (one drop)
were added to sodium 6-bromohexanesulfonate (5.00 g, 18.7 mmol) prepared
by a process described in Org. Synth., Coll. Vol. II, 558 or WO95/19345
Pamphlet. The mixture was refluxed for 4 hours. The reaction mixture was
concentrated in vacuo. The concentrate was diluted with benzene (50 ml).
The resulting solution was washed twice with water (15 ml) and then with
brine (10 ml), and thereafter dried over calcium chloride. The solvent was
removed by evaporation in vacuo. Crude 6-bromohexanesulfonyl chloride
(1.61 g) was obtained as a pale yellow oil.
(1) IR vmax (neat) cm.sup.1 : 1360, 1160 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.6 H.sub.12 BrClO.sub.2 S) EI: m/z 263
[M+1].sup.+, CI: m/z 263 [M+1].sup.+
(3) EI-HRMS (C.sub.6 H.sub.12 BrClO.sub.2 S+H.sup.+)
Calculated: 262.9508, Found: 262.9509
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.56 (4H, m, CH.sub.2 x2), 1.92 (2H,
m, BrCH.sub.2 CH.sub.2), 2.09 (2H, m, SCH.sub.2 CH.sub.2), 3.43 (2H, t,
J=6.6 Hz, BrCH.sub.2), 3.69 (2H, t, J=7.8 Hz, SCH.sub.2)
Preparation Example 3
Preparation of N-Cyclopropyl-6-Bromohexanesulfonamide
6-Bromohexanesulfonyl chloride (1.78 g, 6.78 mmol) obtained in Preparation
Example 2 was added dropwise to a solution of diethyl ether (10 ml) and
cyclopropylamine (774 mg, 13.56 mmol), with stirring under ice-cooling.
Thereafter, the mixture was stirred at the same temperature for 20
minutes. The reaction mixture was washed twice with water (10 ml) and then
with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by evaporation in vacuo. The crude
product was purified by column chromatography on silica gel with ethyl
acetate-n-hexane (1:4)-(1:3), to give
N-cyclopropyl-6-bromohexanesulfonamide (1.52 g) as a colorless waxy
product.
(1) IR vmax (neat) cm.sup.-1 : 3250 (NH), 1310, 1140 (SO.sub.2)
(2) Mass Spectroscopy (CgH.sub.18 BrNO.sub.2 S) EI: m/z 283 [M].sup.+
(3) EI-HRMS (CgH.sub.18 BrNO.sub.2 S)
Calculated: 283.0240, Found: 283.0246
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.65-0.79 (4H, m, CHCH.sub.2 x2),
1.51 (4H, m, BrCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2), 1.75-1.94 (4H, m,
BrCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.56-2.62 (1H, m, CH), 3.07-3.12
(2H, m, SCH.sub.2), 3.43 (2H, t, J=6.7 Hz, BrCH.sub.2), 4.66 (1H, brs, NH)
Preparation Example 4
Preparation of N-(2-Hydroxvethyl)6-chlorohexanesulfonamide
A diethyl ether solution (15 ml) of 6-chlorohexanesulfonyl chloride (3.29
g, 15 mmol) was added dropwise to a suspension of diethyl ether (15 ml)
and ethanolamine (2.02 g, 33 mmol) under ice-cooling. Thereafter, the
mixture was stirred at room temperature for 1 hour. Water was added to the
reaction mixture. The resulting solution was extracted with ethyl acetate
(50 ml). The extract was dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by evaporation in vacuo. The crude
product was purified by column chromatography on silica gel with
chloroform-methanol (20:1). A by-product
[N,O-bis(6-chlorohexanesulfonyl)ethanolamine] was obtained from a first
eluted fraction in the amount of 0.35 g, and
N-(2-hydroxyethyl)-6-chlorohexanesulfonamide was obtained from a second
eluted fraction as a colorless oil in the amount of 3.05 g.
(1) IR vmax (neat) cm.sup.-1 : 3492 (OH), 3293 (NH), 1318, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.8 H.sub.18 ClNO.sub.3 S) EI: m/z 244
[M+1].sup.+, CI: m/z 244 [M+1].sup.+
(3) EI-HRMS (C.sub.8 H.sub.18 ClNO.sub.3 S+H.sup.+)
Calculated: 244.0773, Found: 244.0781
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.42-1.61 (4H, m, ClCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.81 (4H, m, ClCH.sub.2 CH.sub.2, SCH.sub.2
CH.sub.2), 2.38 (1H, t, J=5.1 Hz, OH), 3.05-3.10 (2H, m, SCH.sub.2), 3.28
(2H, q, J=5.2 Hz, NCH.sub.2), 3.55 (2H, t, J=6.5 Hz, ClCH.sub.2), 3.78
(2H, q, J=5.1 Hz, OCH.sub.2), 4.96 (1H, t, J=5.2 Hz, NH)
Preparation Example 5
Preparation of N-(2-Hydroxyethyl)-5-chloroPentanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 4
except for using 5-chloropentanesulfonyl chloride (3.08 g, 15 mmol) in
place of 6-chlorohexanesulfonyl chloride in Preparation Example 4, to give
a by-product [N,O-bis(5-chloropetanesulfonyl)ethanolamine] from a first
eluted fraction in the amount of 0.55 g and
N-(2-hydroxyethyl)-5-chloropentanesulfonamide from a second eluted
fraction as a colorless oil in the amount of 2.61 g.
(1) IR vmax (neat) cm.sup.-1 : 3494 (OH), 3295 (NH), 1318, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.7 H.sub.16 CLNO.sub.3 S) EI: m/z 230
[M+1].sup.+, CI: m/z 230 [M+1].sup.+
(3) EI-HRMS (C.sub.7 H.sub.1 ClNO.sub.3 S+H*)
Calculated: 230.0617, Found: 230.0615
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.54-1.68 (2H, m, ClCH.sub.2
CH.sub.2 CH.sub.2), 1.79-1.93 (4H, m, ClCH.sub.2 CH.sub.2, SCH.sub.2
CH.sub.2), 2.36 (1H, brs, OH), 3.09 (2H, t, J=8.0 Hz, SCH.sub.2), 3.29
(2H, q, J=4.9 Hz, NCH.sub.2), 3.57 (2H, t, J=6.5 Hz, ClCH.sub.2), 3.78
(2H, brd, J=4.5 Hz, OCH.sub.2), 4.97 (1H, m, NH)
Preparation Example 6
Preparation of N-(2-Hydroxyethyl)-12-bromododecanesulfonamide
Ethanolamine (0.67 g, 11 mmol) was reacted with 12-bromododecanesulfonyl
chloride (1.74 g, 5 mmol) in the same manner as in Preparation Example 4,
to give N-(2-hydroxyethyl)-12-bromododecanesulfonamide (1.37 g) as
colorless crystals.
(1) Melting Point: 62.degree.-63.degree. C.
(2) IR vmax (KBr) cm.sup.-1 : 3537 (OH), 3298 (NH), 1322, 1127 (SO.sub.2)
(3) Mass Spectroscopy (C.sub.14 H.sub.30 BrNO.sub.3 S) EI: m/z 372
[M+1].sup.+, CI: m/z 372 [M+1].sup.+
(4) EI-HRMS (Cl.sub.4 H.sub.30 BrNO.sub.3 S+H.sup.+)
Calculated: 372.1207, Found: 372.1200
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.26-1.51 (16H, m, BrCH.sub.2
CH.sub.2 (CH.sub.2).sub.8 CH.sub.2 CH.sub.2 S), 1.76-1.93 (4H, m,
BrCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.05-2.13 (1H, m, OH), 3.0-3.09
(2H, m, SCH.sub.2), 3.29 (2H, q, J=4.9 Hz, NCH.sub.2), 3.42 (2H, t, J=6.9
Hz, BrCH.sub.2), 3.79 (2H, q, J=5.0 Hz, OCH.sub.2), 4.71-4.79 (1H, m, NH)
Preparation Example 7
Preparation of N-(3-Hydroxypropyl)-6-chlorohexanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 4
except for using n-propanolamine (2.48 g, 33 mmol) in place of
ethanolamine in Preparation Example 4, to give a by-product
[N,O-bis(6-chlorohexanesulfonyl)propanolamine] from a first eluted
fraction in the amount of 0.85 g, and
N-(3-hydroxypropyl)-6-chlorohexanesulfonamide from a second eluted
fraction as a colorless waxy product in the amount of 2.86 g.
(1) IR vmax (neat) cm.sup.- : 3447 (OH), 3244 (NH), 1330, 1136 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.9 H.sub.2 OClNO.sub.3 S) EI: m/z 258
[M+1].sup.+, CI: m/z 258 [M+1].sup.+
(3) EI-HRMS (C.sub.9 H.sub.20 ClNO.sub.3 S+H.sup.+)
Calculated: 258.0929, Found: 258.0936
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.44-1.56 (4H, m, ClCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.74-1.89 (6H, m, ClCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2, NHCH.sub.2 CH.sub.2), 1.98 (1H, t, J=5.1 Hz, OH),
3.02-3.07 (2H, m, SCH.sub.2), 3.30 (2H, q, J=6.2 Hz, NCH.sub.2), 3.56 (2H,
t, J=6.5 Hz, ClCH.sub.2), 3.82 (2H, q, J=5.1 Hz, OCH.sub.2), 4.79 (1H, t,
J=6.2 Hz, NH)
Preparation Example 8
Preparation of N-(3-Hydroxypropyl)-5-chloropentanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 4
except for using 5-chloropentanesulfonyl chloride (3.08 g, 15 mmol) in
place of 6-chlorohexanesulfonyl chloride, and n-propanolamine (2.48 g, 33
mmol) in place of ethanolamine in Preparation Example 4, to give a
by-product [N,O-bis(5-chloropetanesulfonyl)propanolamine] from a first
eluted fraction in the amount of 0.64 g and
N-(3-hydroxypropyl)-5-chloropentanesulfonamide from a second eluted
fraction as a colorless waxy product in the amount of 2.76 g.
(1) IR vmax (neat) cm.sup.-1 : 3500-3200 (OH, NH), 1321, 1135 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.8 H.sub.18 ClNO.sub.3 S) EI: m/z
244[M+1].sup.+, CI: m/z 244 [M+1].sup.+
(3) EI-HRMS (C.sub.8 H,.sub.8 ClNO.sub.3 S+H.sup.+)
Calculated: 244.0773, Found: 244.0777
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.54-1.67 (2H, m, ClCH.sub.2
CH.sub.2 CH.sub.2), 1.78-1.91 (6H, m, ClCH.sub.2 CH.sub.2, SCH.sub.2
CH.sub.2, NCH.sub.2 CH.sub.2), 2.01 (1H, m, OH), 3.05 (2H, t, J=8.0 Hz,
SCH.sub.2), 3.30 (2H, q, J=6.2 Hz, NCH.sub.2), 3.57 (2H, t, J=6.4 Hz,
ClCH.sub.2), 3.82 (2H, brd, J=4.9 Hz, OCH.sub.2), 4.84 (1H, m, NH)
Preparation Example 9
Preparation of N,N-Dimethyl-6-chlorohexanesulfonamide
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a
solution of diethyl ether (60 ml) and a 12% acetonitrile solution of
dimethylamine (24.8 g, 66 mmol) with stirring under ice-cooling.
Thereafter, the mixture was stirred at the same temperature for 20
minutes. The reaction mixture was concentrated in vacuo. Thereafter, the
concentrate was diluted with diethyl ether (60 ml). The resulting solution
was washed twice with water (10 ml) and then with brine (10 ml), and
thereafter dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The crude product was
purified by column chromatography on silica gel with ethyl
acetate-n-hexane (1:4), to give N,N-dimethyl-6-chlorohexanesulfonamide
(6.59 g) as a pale yellow oil.
(1) IR vmax (neat) cm.sup.-1 : 1335, 1143 (SO.sub.2)
(2) Mass Spectroscopy (CaHl,ClNO.sub.2 S) EI: m/z 228 [M+1].sup.+, CI: m/z
228 [M+1].sup.+
(3) EI-HRMS (C.sub.8 H.sub.18 ClNO.sub.2 S+H.sup.+)
Calculated: 228.0824, Found: 228.0824
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.41-1.60 (4H, m, ClCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.71-1.88 (4H, m, ClCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2), 2.87 (6H, s, CH.sub.3 x2), 2.89-2.94 (2H, m,
SCH.sub.2), 3.54 (2H, t, J=6.6 Hz, ClCH.sub.2)
Preparation Example 10
Ppreparation of N,N-Dimethyl-5-chloropentanesulfonamide
A 50% aqueous solution of dimethylamine (5.95 g, 66 mmol) was added
dropwise to a solution of diethyl ether (60 ml) and
5-chloropentanesulfonyl chloride (6.15 g, 30 mmol) with stirring under
ice-cooling. Thereafter, the mixture was stirred at the same temperature
for 20 minutes. The reaction solution was washed twice with water (10 ml)
and then with brine (10 ml), and thereafter dried over anhydrous magnesium
sulfate. Subsequently, the solvent was removed by evaporation in vacuo.
The crude product was purified by column chromatography on silica gel with
ethyl acetate-n-hexane (1:4), to give
N,N-dimethyl-5-chloropentanesulfonamide (6.10 g) as a pale yellow oil.
(1) IR vmax (neat) cm.sup.-1 : 1334, 1145 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.7 H.sub.16 ClNO.sub.2 S) EI: m/z 214
[M+1].sup.+, CI: m/z 214 [M+1].sup.+
(3) EI-HRMS (C.sub.7 H.sub.16 ClNO.sub.2 S+H.sup.+)
Calculated: 214.0667, Found: 214.0658
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.59-1.67 (2H, m, ClCH.sub.2
CH.sub.2 CH.sub.2), 1.80-1.93 (4H, m, ClCH.sub.2 CH.sub.2, SCH.sub.2
CH.sub.2), 2.90 (6H, s, CH.sub.3 x2), 2.91-2.97 (2H, m, SCH.sub.2), 3.57
(2H, t, J=6.5 Hz, ClCH.sub.2)
Preparation Example 11
Preparation of N,N-Diethyl-6-chlorohexanesulfonamide
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a
solution of diethyl ether (60 ml) and diethylamine (4.83g, 66 mmol) with
stirring under ice-cooling. Thereafter, the mixture was stirred at the
same temperature for 20 minutes. The reaction mixture was washed twice
with water (10 ml) and then with brine (10 ml), and thereafter dried over
anhydrous magnesium sulfate. Subsequently, the solvent was removed by
evaporation In vacuo. The crude product was purified by column
chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give
N,N-diethyl-6-chlorohexanesulfonamide (7.12 g) as a pale yellow oil.
(1) IR vmax (neat) cm.sup.-1 : 1329, 1140 (SO.sub.2)
(2) Mass Spectroscopy (ClOH.sub.22 ClNO.sub.2 S) EI: m/z 255 [M].sup.+
(3) EI-HRMS (ClOH.sub.22 ClNO.sub.2 s)
Calculated: 255.1059, Found: 255.1064
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21 (6H, t, J=7.1 Hz, CH.sub.3 x2),
1.39-1.55 (4H, m, ClCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2), 1.73-1.87 (4H,
m, ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.89-2.95 (2H, m, SCH.sub.2),
3.30 (4H, q, J=7.1 Hz, CH.sub.3 CH.sub.2 x2), 3.54 (2H, t, J=6.5 Hz,
ClCH.sub.2)
Preparation Example 12
Preparation of N,N-Diethyl-5-chloropentanesulfonamide
The reaction was carried out in the same manner as in Preparation Example
11 except for using 5-chloropentanesulfonyl chloride (6.15g, 30 mmol) in
place of 6-chlorohexanesulfonyl chloride in Preparation Example 11, to
give N,N-diethyl-5-chloropentanesulfonamide (6.78 g) as a pale yellow oil.
(1) IR vmax (neat) cm.sup.-1 : 1329, 1140 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.9 H.sub.20 ClNO.sub.2 S) EI: m/z 242
[M+1].sup.+, CI: m/z 242 [M+1].sup.+
(3) EI-HRMS (C.sub.9 H.sub.20 ClNO.sub.2 S+H.sup.+)
Calculated: 242.0980, Found: 242.0976
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22 (6H, t, J=7.1 Hz, CH.sub.3 x2),
1.58-1.62 (2H, m, ClCH.sub.2 CH.sub.2 CH.sub.2), 1.80-1.88 (4H, m,
ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.91-2.96 (2H, m, SCH.sub.2),
3.31 (4H, q, J=7.1 Hz, CH.sub.3 CH.sub.2 x2), 3.56 (2H, t, J=6.5 Hz,
ClCH.sub.2)
Preparation Example 13
Preparation of N-n-Butyl-N-methyl-6-chlorohexanesulfonamide
The reaction was carried out in the same manner as in Preparation Example
11 except for using N-methyl-n-butylamine (5.75g, 66 mmol) in place of
diethylamine in Preparation Example 11, to give
N-n-butyl-N-methyl-6-chlorohexanesulfonamide (7.56 g) as a pale yellow
oil.
(1) IR vmax (neat) cm.sup.-1 : 1333, 1142 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.11 H.sub.24 ClNO.sub.2 S) EI: m/z 270
[M+1].sup.+, CI: m/z 270 [M+1].sup.+
(3) EI-HRMS (C.sub.11 H.sub.24 ClNO.sub.2 S+H.sup.+)
Calculated: 270.1293, Found: 270.1281
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, t, J=7.3 Hz, CH.sub.3
CH.sub.2), 1.33-1.41 (2H, m, CH.sub.3 CH.sub.2), 1.47-1.61 (6H, m,
ClCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2, NCH.sub.2 CH.sub.2), 1.79-1.86 (4H,
m, ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), 2.87 (3H, s, NCH.sub.3),
2.90-2.95 (2H, m, SCH.sub.2), 3.18 (2H, t, J=7.4 Hz, NCH.sub.2), 3.55 (2H,
t, J=6.6 Hz, ClCH.sub.2)
Preparation Example 14
Preparation of N-n-Butyl-N-methyl-5-chloropentanesulfonamide
The reaction was carried out in the same manner as in Preparation Example
11 except for using N-methyl-n-butylamine (5.75g, 66 mmol) in place of
diethylamine, and 5-chloropentanesulfonyl chloride (6.15g, 30 mmol) in
place of 6-chlorohexanesulfonyl chloride in Preparation Example 11, to
give N-n-butyl-N-methyl-5-chloropentanesulfonamide (7.12 g) as a pale
yellow oil.
(1) IR vmax (neat) cm.sup.- : 1333, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.10 H.sub.22 ClNO.sub.2 S) EI: m/z 256
[M+1].sup.+, CI: m/z 256 [M+1].sup.+
(3) EI-HRMS (ClOH.sub.22 ClNO.sub.2 S+H.sup.+)
Calculated: 256.1137, Found: 256.1137
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.96 (3H, t, J=7.3 Hz, CH.sub.3
CH.sub.2), 1.33-1.41 (2H, m, CH.sub.3 CH.sub.2), 1.54-1.63 (4H, m,
ClCH.sub.2 CH.sub.2 CH.sub.2, NCH.sub.2 CH.sub.2), 1.79-1.88 (4H, m,
ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2), J=2.87 (3H, s, NCH.sub.3),
2.88-2.96 (2H, m, SCH.sub.2), 3.18 (2H, t, J=7.4 Hz, NCH.sub.2), 3.56 (2H,
t, J=6.5 Hz, ClCH.sub.2)
Preparation Example 15
Preparation of (3-Chlorophenyl)phenylmethylamine hydrochloride
In accordance with the method described in Bull. Soc. Chim. France, 352-359
(1959), 3-chlorobenzophenone (43.33g, 0.2 mol) and ammonium formate
(63.06g, 1.0 mol) were refluxed for 3 hours in nitrobenzene (250 ml).
After cooling the refluxed mixture to room temperature, the reaction
solution was concentrated in vacuo. A 15% HCl-ethanol solution (420 ml)
was added to the residue, and the mixture was refluxed for 2 hours. The
reaction solution was concentrated in vacuo. Thereafter, diethyl ether was
added thereto, and the crude product was collected by filtration.
Thereafter, (3-chlorophenyl)phenylmethylamine hydrochloride (21.86 g) was
recrystallized from water as colorless needles.
(1) Melting Point: 263.degree.-265.degree. C.
(2) Elemental Analysis (as C.sub.13 H.sub.12 ClN HCl)
Calculated: C, 61.43; H, 5.15; N, 5.51
Found: C, 61.36; H, 5.03; N, 5.50
Preparation Example 16
Preparation of +(+)-(3-Chlorophenyl)phenylmethylamine
(3-Chlorophenyl)phenylmethylamine (9.42g, 43.3 mmol) and (+)-tartaric acid
(6.50g, 43.3 mmol) were dissolved in water (40 ml) with heating.
Thereafter, the precipitated crude crystals obtained by allowing to cool
the reaction solution to room temperature were collected by filtration.
The resulting crystals were purified by repeatedly recrystallizing from
water, to give (+)-(3-chlorophenyl)phenylmethylamine (+)-tartrate (4.28
g). In order to determine the optical purity of
(+)-(3-chlorophenyl)phenylmethylamine (+)-tartrate, HPLC analysis was
carried out. Its analytical conditions are as follows.
HPLC Analytical Conditions
Column: ULTRON ES--OVM, 4.6 mm.times.150 mm (5 .mu.m)
Mobile Phase: acetonitrile:phosphate buffer (pH 7.0)=12.5:87.5
Flow Rate: 1.0 ml/min.
Detection: at UV 254 nm
Retention Time
[(3-chlorophenyl)phenylmethylamine hydrochloride (racemate)]:
12.1 min. [50%, (-)-form]
13.4 min. [50%, (+)-form]
Subject: 12.2 min. (1.1%), 13.4 min. (98.9%)
From the above results, it was found that the optical purity of the
(+)-(3-chlorophenyl)phenylmethylamine (+)-tartrate obtained in Preparation
Example 16 was 97.8% ee.
Next, (+)-(3-chlorophenyl)phenylmethylamine (+)tartrate (4.28 g) was
suspended in chloroform (40 ml), and 28%-aqueous ammonia was added thereto
to neutralize the mixture. Thereafter, the chloroform layer was separated
therefrom. The extract was dried over anhydrous magnesium sulfate, and the
solvent was removed by evaporation in vacuo, to give
(+)-(3-chlorophenyl)phenylmethylamine (2.45 g) as a pale yellow oil.
(1) [.alpha.].sub.D.sup.26 +19.2.degree. (c=5.0, ethanol)
Preparation Example 17
Preparation of (+)
-1-[(3-Chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine
(+)-(3-Chlorophenyl)phenylmethylamine (2.45 g, 11.27 mmol) and
N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3.67g, 12.39 mmol) were
refluxed for 4 hours in N-ethyldiisopropylamine (15 ml). The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water and then dried over anhydrous magnesium sulfate. Thereafter,
the crude product obtained by removing the solvent by evaporation in vacuo
was purified by column chromatography on silica gel with chloroform, to
give
(+)-1-[(3-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazin
e (4.82 g) as colorless prisms.
(1) Melting Point: 217.degree.-218.degree. C. (acetone)
(2) Elemental Analysis (as C.sub.24 H.sub.25 ClN.sub.2 O.sub.2 S)
Calculated: C, 65.36; H, 5.72; N, 6.35
Found: C, 65.34; H, 5.85; N, 6.27
(3) [.alpha.].sub.D.sup.27 +26.40 (c=3.0, chloroform)
Preparation Example 18
Preparation of (+)-1-[(3-Chlorophenyl)phenylmethyl]piperazine
(+)-1-[(3-Chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine
(4.62 g, 10.48 mmol) was stirred in 30% hydrobromic acid-acetic acid
solution (20 ml) in the presence of 4-hydroxybenzoic acid (5.06g, 36.66
mmol) at room temperature for two days. 28%-Aqueous ammonia was added to
the reaction mixture, and the resulting mixture was extracted with
chloroform. The chloroform layer was washed with water and then dried over
anhydrous magnesium sulfate. Thereafter, the crude product obtained by
removing the solvent by evaporation in vacuo was purified by column
chromatography on silica gel with chloroform-methanol (20:1), to give
(+)-1-[(3-chlorophenyl)phenylmethyl]piperazine (2.67 g).
(1) Mass Spectroscopy (C.sub.17 H.sub.19 ClN.sub.2) EI: m/z 286 [M].sup.+
(2) EI-HRMS (C.sub.17 H.sub.19 ClN.sub.2)
Calculated: 286.1236, Found: 286.1235
(3) [.alpha.].sub.D.sup.27 +18.3.degree. (c=2.145, methanol)
Next, in order to determine the optical purity of
(+)-1-[(3-chlorophenyl)phenylmethyl]piperazine, HPLC analysis was carried
out. Its analytical conditions are as follows.
HPLC Analytical Conditions
Column: ULTRON ES--OVM, 4.6 mm.times.150 mm (5 .mu.m)
Mobile Phase: acetonitrile:acetate buffer (pH 5.1)=1:9
Flow Rate: 1.2 ml/min.
Detection: at UV 254 nm
Retention Time
[1-[(3-chlorophenyl)phenylmethyl]piperazine (racemate)]:
6.7 min. [50%, (+)-form]
7.9 min. [50%, (-)-form]
Subject: 5.8 min. (98.7%), 8.0 min. (1.3%)
From the above results, it was found that the optical purity of the
(+)-1-[(3-chlorophenyl)phenylmethyl]piperazine obtained in Preparation
Example 18 was 97.4% ee.
Preparation Example 19
Preparation of (-)-(3-Chlorophenyl)phenylmethylamine
(3-Chlorophenyl)phenylmethylamine (9.25g, 42.5 mmol) and (-)-tartaric acid
(7.02 g, 46.7 mmol) were dissolved in water (40 ml) with heating.
Thereafter, the precipitated crude crystals obtained by allowing to cool
the reaction solution to room temperature were collected by filtration.
The resulting crystals were purified by repeatedly recrystallizing from
water, to give (-)-(3-chlorophenyl)phenylmethylamine (-)-tartrate (4.58
g).
In order to determine the optical purity of
(-)-(3-chlorophenyl)phenylmethylamine (-)-tartrate, HPLC analysis was
carried out in accordance with the method in Preparation Example 16. As a
result, it was found that the optical purity of the
(-)-(3-chlorophenyl)phenylmethylamine (-)-tartrate was 97.6% ee.
Next, (-)-(3-chlorophenyl)phenylmethylamine (-)tartrate (4.50 g) was
suspended in chloroform (40 ml). 28%-Aqueous ammonia was added to the
reaction mixture to neutralize the mixture. Thereafter, the chloroform
layer was separated therefrom, and the extract was dried over anhydrous
magnesium sulfate. Thereafter, the solvent was removed by evaporation in
vacuo, to give (-)-(3-chlorophanyl)phenylmethylamine (2.63 g) as a pale
yellow oil.
(1) [.alpha.].sub.D.sup.26 19.2.degree. (c=5.0, ethanol)
Preparation Example 20
Preparation of
(-)-1-[(3-Chlorophenyl)phenylmethyl]-4-[4-methylphenyl)sulfonyl]piperazine
(-)-(3-Chlorophenyl)phenylmethylamine (2.63 g, 12.1 mmol) and
N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3.94 g, 13.3 mmol) were
refluxed for 4 hours in N-ethyldiisopropylamine (15 ml). The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water and then dried over anhydrous magnesium sulfate. Thereafter,
the crude product obtained by removing the solvent by evaporation in vacuo
was purified by column chromatography on silica gel with chloroform, to
give (-)
-1-[(3-chlorophenyl)phenylmethyl]-4-[4-methylphenyl)sulfonyl]piperazine
(5.20 g) as colorless prisms.
(1) Melting Point: 215.degree.-217.degree. C. (acetone)
(2) Elemental Analysis (as C.sub.24 H.sub.25 ClN.sub.2 O.sub.2 S)
Calculated: C, 65.36; H, 5.72; N, 6.35
Found: C, 65.23; H, 5.62; N, 6.34
(3) [.alpha.].sub.D.sup.27 25.6.degree. (c=3.0, chloroform)
Preparation Example 21
Preparation of (-)-1-[(3-Chlorophenyl)phenylmethyl]piperazine
(-)-1-1(3-Chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine
(5.00g, 11.3 mmol) was stirred in 30% hydrobromic acid-acetic acid
solution (20 ml) in the presence of 4-hydroxybenzoic acid (5.48 g, 39.7
mmol) at room temperature for two days. 28%-Aqueous ammonia was added to
the reaction mixture, and the resulting mixture was extracted with
chloroform. The chloroform layer was washed with water and then dried over
anhydrous magnesium sulfate. Thereafter, the crude product obtained by
removing the solvent by evaporation in vacuo was purified by column
chromatography on silica gel with chloroform-methanol (20:1), to give
(-)-1-[(3-chlorophenyl)phenylmethyl]piperazine (2.60 g).
(1) Mass Spectroscopy (C.sub.17 H.sub.19 ClN.sub.2) EI: m/z 286 [M].sup.+
(2) EI-HRMS (C.sub.17 H.sub.19 ClN.sub.2)
Calculated: 286.1236, Found: 286.1239
(3) [.alpha.].sub.D.sup.27 18.3.degree. (c=2.145, methanol)
In order to determine the optical purity of the resulting
(-)-1-[(3-chlorophenyl)phenylmethyl]piperazine, HPLC analysis was carried
out in accordance with the method in Preparation Example 18. As a result,
it was found that the optical purity of the
(-)-1-[(3-chlorophenyl)phenylmethyl]piperazine was 97.6% ee.
Preparation Example 22
Preparation of N-(4-Hydroxybutyl)-6-chlorohexanesulfonamide
A solution of ethyl acetate (15 ml) and 6-chlorohexanesulfonyl chloride
(3.29g, 15 mmol) was added dropwise to a suspension of ethyl acetate (15
ml) of 4-amino-1-butanol (2.94g, 33 mmol) under ice-cooling. Thereafter,
the mixture was stirred at room temperature for 1 hour. Water was added to
the reaction mixture, and the mixture was extracted with ethyl acetate (50
ml). The extract was dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by evaporation in vacuo. The crude
product was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (2.4 g) as colorless
crystals.
(1) Melting Point: 61.degree.-62.degree. C. (ethyl acetate)
(2) IR vmax (KBr) cm.sup.-1 : 3412 (OH), 3276 (NH), 1332, 1133 (SO.sub.2)
(3) Mass Spectroscopy (ClOH.sub.22 ClNO.sub.3 S) EI: m/z 272 [M+1].sup.+,
CI: m/z 272 [M+1].sup.+
(4) EI-HRMS (C.sub.10 H.sub.22 ClNO.sub.3 +H.sup.+)
Calculated: 272.1086, Found: 272.1086
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.42-1.57 (4H, m, ClCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.61-1.89 (9H, m, ClCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2, NHCH.sub.2 CH.sub.2 CH.sub.2, OH), 3.00-3.05 (2H, m,
SCH.sub.2), 3.17 (2H, q, J=6.2 Hz, NCH.sub.2 x2), 3.55 (2H, t, J=6.5 Hz,
ClCH.sub.2), 3.70 (2H, brs, OCH.sub.2), 4.77 (1H, brs, NH)
(6) Elemental Analysis (C.sub.10 H.sub.22 ClNO.sub.3 S)
Calculated: C, 44.19; H, 8.16; N, 5.15
Found: C, 44.22; H, 8.12; N, 4.99
Preparation Example 23
Preparation of N-(4-Hydroxybutyl)-5-chloropentanesulfonamide
The reaction was carried out in the same manner as in Preparation Example
22 except for using 5-chloropentanesulfonyl chloride (3.08g, 15 mmol) in
place of 6-chlorohexanesulfonyl chloride in Preparation Example 22, to
give a desired compound (2.19 g) as colorless crystals.
(1) Melting Point: 740-75.degree. C. (ethyl acetate)
(2) IR vmax (KBr) cm.sup.-1 : 3400 (OH), 3275 (NH), 1333, 1130 (SO.sub.2)
(3) Mass Spectroscopy (C.sub.9 H.sub.20 ClNO.sub.3 S) EI: m/z 258
[M+1].sup.+, CI: m/z 258 [M+1].sup.+
(4) EI-HRMS (C.sub.9 H.sub.20 ClNO.sub.3 +H.sup.+)
Calculated: 258.0929, Found: 258.0929
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.54-1.76 (6H, m, ClCH.sub.2
CH.sub.2 CH.sub.2, NHCH.sub.2 CH.sub.2 CH.sub.2), 1.79-1.91 (5H, m,
ClCH.sub.2 CH.sub.2, SCH.sub.2 CH.sub.2, OH), 3.04 (2H, t, J=8.0 Hz,
SCH.sub.2), 3.17 (2H, q, J=6.2 Hz, NCH.sub.2), 3.57 (2H, t, J=6.5 Hz,
ClCH.sub.2), 3.70 (2H, brs, OCH.sub.2), 4.79 (1H, m, NH)
(6) Elemental Analysis (C.sub.9 H.sub.20 ClNO.sub.3 S)
Calculated: C, 41.93; H, 7.82; N, 5.43
Found: C, 41.89; H, 7.56; N, 5.22
Preparation Example 24
Preparation of N-Cyclopropyl-10-bromodecanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 3
except for using 10-bromodecanesulfonyl chloride (450 mg, 1.41 mmol) in
place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (177 mg,
3.10 mmol), to give N-cyclopropyl-10-bromodecanesulfonamide (467 mg) as
colorless crystals.
(1) Melting Point: 57.degree.-60.degree. C. (chloroform-n-hexane)
(2) IR vmax (KBr) cm.sup.-1 : 3273 (NH), 1317, 1135 (SO.sub.2)
(3) Mass Spectroscopy (C.sub.13 H.sub.26 BrNO.sub.2 S) EI: m/z 340
[M+1].sup.+, CI: m/z 340 [M+1].sup.+
(4) EI-HRMS (C.sub.13 H.sub.26 BrNO.sub.2 S+H.sup.+)
Calculated: 340.0945, Found: 340.0938
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.67-0.79 (4H, m, CHCH.sub.2 x2),
1.32-1.48 (12H, m, CH.sub.2 x6), 1.79-1.93 (4H, m, BrCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2), 2.56-2.62 (1H, m, CH), 3.06-3.11 (2H, m, SCH.sub.2),
3.42 (2H, t, J=6.8 Hz, BrCH.sub.2), 4.60 (1H, brs, NH)
(6) Elemental Analysis (C.sub.13 H.sub.26 BrNO.sub.2 S)
Calculated: C, 45.88; H, 7.70; N, 4.12
Found: C, 46.03; H, 7.59; N, 4.27
Preparation Example 25
Preparation of N-Cyclopropyl-1-bromoundecanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 3
except for using 11-bromoundecanesulfonyl chloride (2.29g, 6.85 mmol) in
place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (860 mg,
15.1 mmol), to give N-cyclopropyl-11-bromoundecanesulfonamide (2.33 g) as
colorless crystals.
(1) Melting Point: 71.degree.-73.degree. C. (chloroform-n-hexane)
(2) IR vmax (KBr) cm.sup.-1 : 3274 (NH), 1317, 1135 (SO.sub.2)
(3) Mass Spectroscopy (C.sub.14 H.sub.28 BrNO.sub.2 S) EI: m/z 354
[M+1].sup.+, CI: m/z 354 [M+1].sup.+
(4) EI-HRMS (C.sub.14 H.sub.28 BrNO.sub.2 S+H.sup.+)
Calculated: 354.1101, Found: 354.1092
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.65-0.79 (4H, m, CHCH.sub.2 x2),
1.31-1.48 (14H, m, CH.sub.2 x7), 1.74-1.92 (4H, m, BrCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2), 2.57-2.62 (1H, m, CH), 3.06-3.11 (2H, m, SCH.sub.2),
3.42 (2H, t, J=6.8 Hz, BrCH.sub.2), 4.61 (1H, brs, NH)
Preparation Example 26
Preparation of N-Cyclopropyl-12-bromododecanesulfonamide
The reaction was carried out in the same manner as in Preparation Example 3
except for using 12-bromododecanesulfonyl chloride (2.92g, 8.4 mmol) in
place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (1.08g, 18.5
mmol), to give N-cyclopropyl-12-bromododecanesulfonamide (2.99 g) as
colorless crystals.
(1) Melting Point: 71.degree.14 73.degree. C. (n-hexane)
(2) IR vmax (KBr) cm.sup.-1 : 3274 (NH), 1318, 1135 (SO.sub.2)
(3) Mass Spectroscopy (Cl.sub.5 H.sub.30 BrNO.sub.2 S) EI: m/z 368
[M+1].sup.+, CI: m/z 368 [M+1].sup.+
(4) EI-HRMS (C.sub.15 H.sub.30 BrNO.sub.2 S+H.sup.+)
Calculated: 368.1257, Found: 368.1261
(5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.66-0.79 (4H, m, CHCH.sub.2 x2),
1.30-1.50 (16H, m, CH.sub.2 x8), 1.74-1.92 (4H, m, BrCH.sub.2 CH.sub.2,
SCH.sub.2 CH.sub.2), 2.57-2.63 (1H, m, CH), 3.06-3.11 (2H, m, SCH.sub.2),
3.43 (2H, t, J=6.8 Hz, BrCH.sub.2), 4.58 (1H, brs, NH)
(6) Elemental Analysis (C.sub.15 H.sub.30 BrNO.sub.2 S)
Calculated: C, 48.90; H, 8.21; N, 3.80
Found: C, 49.18; H, 8.36; N, 4.08
Example 1
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed
in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (884.7 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 95.2%).
(1) IR vmax (neat) cm.sup.-1 : 3274 (NH), 1320, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2215, Found: 489.2213
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.65-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.30-1.56 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.76-1.88 (2 H, m, SCH.sub.2 CH.sub.2), 2.35 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.38-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.55-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH),
4.60 (1 H, s, NH), 7.13-7.45 (9 H, m, ArH)
Example 2
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and
N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed
in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (711.3 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 90.8%).
The resulting
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide had physical properties similar to those of
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide obtained in Example 1.
Example 3
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and
N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed
in triethylamine (2 ml) for 4 hours. The reaction mixture was concentrated
in vacuo, and water was added thereto. The mixture was extracted with
chloroform. The chloroform layer was washed with water, and dried over
anhydrous magnesium sulfate. Subsequently, the solvent was removed by
evaporation in vacuo. The resulting crude product was purified by column
chromatography on silica gel chloroform-methanol (20:1), to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (737.8 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 94.1%).
The resulting
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide had physical properties similar to those of
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide obtained in Example 1.
Example 4
[Preparation of
N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (3.00 g, 10.46 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (2.76 g, 11.51 mmol) were refluxed
in N-ethyldiisopropylamine (8 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (4.62 g) as an oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 90.1%).
(1) IR vmax (neat) cm.sup.-1 : 3272 (NH), 1317, 1147 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2215, Found: 489.2217
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.65-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.30-1.57 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.36 (2 H, t, J=7.9 Hz,
NCH.sub.2), 2.39-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.55-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.23 (1 H, s, CH),
4.64 (1 H, s, NH), 7.17-7.40 (9 H, m, ArH)
Example 5
[Preparation of
N-Cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfona
mide]
1-[Bis(4-chlorophenyl)methyl]piperazine (10.00 g, 31.13 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (8.30 g, 34.63 mmol) were refluxed
in N-ethyldiisopropylamine (50 ml) for 7 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfona
mide (14.70 g) as an oil (yield based on
1-[bis(4-chlorophenyl)methyl]piperazine: 95.3%).
(1) IR vmax (neat) cm.sup.-1 : 3273 (NH), 1317, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.35 Cl.sub.2 N.sub.3 O.sub.2 S) EI:
m/z 523 [M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.35 Cl.sub.2 N.sub.3 O.sub.2 S)
Calculated: 523.1825, Found: 523.1823
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.65-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.30-1.56 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.77-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.38-2.52 (8 H, m, NCH.sub.2 CH.sub.2 X2), 2.55-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.21 (1 H, s, CH),
4.61 (1 H, s, NH), 7.23-7.35 (8 H, m, ArH)
Example 6
[Preparation of
N-Cyclopropyl-6-[4-[bis(3-chlorophenyl)methyl]-1-piperazinyl]hexanesulfona
mide]
1-[Bis(3-chlorophenyl)methyl]piperazine (5.00 g, 15.5 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (4.15 g, 17.30 mmol) were refluxed
in N-ethyldiisopropylamine (25 ml) for 7 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[bis(3-chlorophenyl)methyl)]-1-piperazinyl]hexanesulfon
amide (7.73 g) as an oil (yield based on
1-[bis(3-chlorophenyl)methyl]piperazine: 94.7%).
(1) IR vmax (neat) cm.sup.-1 : 3274 (NH), 1317, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.35 Cl.sub.2 N.sub.3 O.sub.2 S) EI:
m/z 523 [M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.35 Cl.sub.2 N.sub.3 O.sub.2 S)
Calculated: 523.1825, Found: 523.1822
(4) .sup.1 H-NMR (CDC1.sub.3) .delta.: 0.66-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.28-1.55 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.35 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.38-2.51 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.55-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.20 (1 H, s, CH),
4.61 (1 H, s, NH), 7.16-7.41 (8 H, m, ArH)
Example 7
[Preparation of
N-Cyclopropyl-6-[4-[bis(4-fluoronhenyl)methyl]-1-piperazinyl]hexanesulfona
mide]
1-[Bis(4-fluorophenyl)methyl]piperazine (8.92 g, 30.0 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (7.91 g, 33.0 mmol) were refluxed
in N-ethyldiisopropylamine (20 ml) for 8 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (50:3), to
give
N-cyclopropyl-6-[4-[bis(4-fluorophenyl)methyl]1-piperazinyl]hexanesulfonam
ide (13.97 g) as a crystalline substance (yield based on
1-[bis(4-fluorophenyl)methyl]piperazine: 94.7%).
(1) IR vmax (neat) cm.sup.-1 : 3273 (NH), 1318, 1151 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.35 F.sub.2 N.sub.3 O.sub.2 S) EI: m/z
491 [M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.35 F.sub.2 N.sub.3 O.sub.2 S)
Calculated: 491.2416, Found: 491.2418
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.66-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.28-1.55 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.37-2.54 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.54-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.23 (1 H, s, CH),
4.60 (1 H, s, NH), 6.93-7.02 (4 H, m, ArH), 7.32-7.39 (4 H, m, ArH)
Example 8
[Preparation of
N-Cyclopropyl-6-[4-[4-chlorophenyl-(2-Pyridyl)methyl[-1-piperazinyl]hexane
sulfonamide]
1-[4-Chlorophenyl-(2-pyridyl)methyl]piperazine (7.90 g, 27.5 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (7.24 g, 30.2 mmol) were refluxed
in N-ethyldiisopropylamine (20 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopropyl-6-[4-[4-chlorophenyl-(2-pyridyl)methyl]-1-piperazinyl]hexane
sulfonamide (6.29 g) as an oil (yield based on
1-[4-chlorophenyl-(2-pyridyl)methyl]piperazine: 92.7%).
(1) IR vmax (neat) cm.sup.-1 : 3271 (NH), 1317, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.35 ClN.sub.4 O.sub.2 S) EI: m/z 490
[M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.35 ClN.sub.4 O.sub.2 S)
Calculated: 490.2167, Found: 490.2170
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.64-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.27-1.55 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.37-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.53-2.62 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.04-3.10 (2 H, m, SCH.sub.2), 4.42 (1 H, s, CH),
4.68 (1 H, s, NH), 7.09-7.66 (7 H, m, ArH), 8.50-8.53 (1 H, m, ArH)
Example 9
[Preparation of
N-Cyclopentyl-6-[4-[4-fluorophenyl-(2-pyridyl)methyl]-1-piperazinyl]hexane
sulfonamide]
1-[4-Fluorophenyl-(2-pyridyl)methyl]piperazine (2.57 g, 9.5 mmol) and
N-cyclopentyl]-6-chlorohexanesulfonamide (2.80 g, 10.5 mmol) were refluxed
in N-ethyldiisopropylamine (8 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-cyclopentyl-6-[4-[4-fluorophenyl-(2-pyridyl)methyl]-1-piperazinyl]hexane
sulfonamide (4.30 g) as an oil (yield based on
1-[4-fluorophenyl-(2-pyridyl)methyl]piperazine: 90.1%).
(1) IR vmax (neat) cm.sup.-1 : 3278 (NH), 1324, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.27 H.sub.39 FN.sub.4 O.sub.2 S) EI: m/z 502
[M].sup.+
(3) EI-HRMS (C.sub.27 H.sub.39 FN.sub.4 O.sub.2 S)
Calculated: 502.2775, Found: 502.2774
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23-1.86 (14 H, m, CH(CH.sub.2
CH.sub.2).sub.2, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2), 1.95-2.06 (2 H, m,
SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.8 Hz, NCH.sub.2), 2.37-2.53 (8 H,
m, NCH.sub.2 CH.sub.2 x2), 2.98-3.03 (2 H, m, SCH.sub.2), 3.70-3.82 (1 H,
m, CHCH.sub.2 CH.sub.2), 4.12 (1 H, d, J=7.6 Hz, NH), 4.43 (1 H, s, CH),
6.92-7.66 (7 H, m, ArH), 8.50-8.54 (1 H, m, ArH)
Example 10
[Preparation of
6-[4-[(3-Chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (500 mg, 1.74 mmol) and
6-chlorohexanesulfonamide (383 mg, 1.92 mmol) synthesized referring to a
process described in J. Org. Chem. 52, 2162 (1987) were refluxed in
N-ethyldiisopropylamine (5 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (100:3),
to give 6-[4-[(3-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide
(749 mg) as a colorless oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 95.4%).
(1) IR vmax (neat) cm.sup.-1 : 3274 (NH), 1324, 1147 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.23 H.sub.32 ClN.sub.3 O.sub.2 S) EI: m/z 449
[M].sup.+
(3) EI-HRMS (C.sub.23 H.sub.32 ClN.sub.3 O.sub.2 S)
Calculated: 449.1902, Found: 449.1897
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-1.57 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.82-1.94 (2 H, m, SCH.sub.2 CH.sub.2), 2.35
(2 H, t, J=8.0 Hz, NCH.sub.2), 2.39-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2),
3.10-3.14 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH), 4.67 (2 H, brs,
NH.sub.2), 7.14-7.45 (9 H, m, ArH)
Example 11
[Preparation of
N-Cyclopropyl-6-[4-(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide fumarate]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (13.03 g, 26.59 mmol) prepared in the same manner as in Example 1
was dissolved in ethanol (100 ml). Fumaric acid (4.01 g, 34.55 mmol) was
added thereto. After dissolving the mixture with heating, the mixture was
cooled in an ice bath to allow the mixture to crystallize. The crystals
were filtered, washed with a small amount of ethanol, and dried at
80.degree. C. in vacuo, to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide fumarate (15.11 g) as colorless prisms (yield based on
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 93.7%).
(1) Melting Point: 186.degree.-188.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S C.sub.4
H.sub.4 O.sub.4)
Calculated: C, 59.44; H, 6.65; N, 6.93
Found: C, 59.22; H, 6.51; N, 7.05
Example 12
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide dimaleate]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (253 mg, 0.52 mmol) prepared in the same manner as in Example 1 was
dissolved in methanol (15 ml). Maleic acid (138 mg, 1.19 mmol) was added
thereto. After dissolving the mixture with heating, the solvent was
removed by evaporation in vacuo. Acetone-diethyl ether was added to the
residue, and the precipitated crystals were collected by filtration. The
crystals were recrystallized from ethyl acetate, to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide dimaleate (189 mg) as colorless prisms (yield based on
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl)hexanesulf
onamide: 50.3%).
(1) Melting Point: 106.degree.-108.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S 2C.sub.4
H.sub.4 O.sub.4)
Calculated: C, 56.54; H, 6.14; N, 5.82
Found: C, 56.56; H, 6.07; N, 5.80
Example 13
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide oxalate]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (1.00 g, 2.04 mmol) prepared in the same manner as in Example 1 was
dissolved in methanol (50 ml). Oxalic acid dehydrate (0.32 g, 2.55 mmol)
was added thereto. After dissolving the mixture with heating, the solvent
was removed by evaporation in vacuo. Acetone was added to the residue, and
the precipitated crystals were collected by filtration. The crystals were
recrystallized from acetone, to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide oxalate (0.85 g) as colorless crystals (yield based on
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 71.8%).
(1) Melting Point: 160.degree.-162.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S C.sub.2
H.sub.2 O.sub.4)
Calculated: C, 57.97; H, 6.60; N, 7.24
Found: C, 58.21; H, 6.76; N, 7.12
Example 14
[Preparation of
N-Cyclopropyl-6-[4-(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide hydrochloride]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (1.00 g, 2.04 mmol) prepared in the same manner as in Example 1 was
dissolved in methanol (10 ml). 2 M hydrochloric acid (factor =1.004) (1.00
ml) was added thereto, and the solvent was then removed by evaporation in
vacuo. Acetone was added to the residue, and the precipitated crystals
were collected by filtration. The crystals were recrystallized from
ethanol-acetone, to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide hydrochloride (0.80 g) as colorless prisms (yield based on
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 74.8%).
(1) Melting Point: 146.degree.-150.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S HCl)
Calculated: C, 59.30; H, 7.08; N, 7.98
Found: C, 59.15; H, 7.04; N, 7.87
Example 15
[Preparation of
N-Cyclopropyl-6-[-4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide dihydrochloride]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (1.00 g, 2.04 mmol) prepared in the same manner as in Example 1 was
dissolved in methanol (10 ml). A 15% HCl-methanol solution was added
thereto to make the solution acidic, and the solvent was then removed by
evaporation in vacuo. Acetone was added to the residue, and the
precipitated crystals were collected by filtration. The crystals were
recrystallized from ethanol, to give
N-cyclopropyl-6-[-4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide dihydrochloride (0.87 g) as colorless prisms (yield based on
N-cyclopropyl-6-[-4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide: 75.7%).
(1) Melting Point: 160.degree.-167.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S 2HCl)
Calculated: C, 55.46; H, 6.80; N, 7.46
Found: C, 55.40; H, 6.94; N, 7.31
Example 16
[Preparation of
N-Cyclopropyl-6-[-4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide dihydrobromide]
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (0.50 g, 1.02 mmol) prepared in the same manner as in Example 1 was
dissolved in methanol (20 ml). A 47% hydrobromic acid solution (0.47 g,
2.75 mmol) was added thereto, and the solvent was then removed by
evaporation in vacuo. Acetone was added to the residue, and the
precipitated crystals were collected by filtration. The crystals were
recrystallized from ethanol-acetone, to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide dihydrobromide (0.46 g) as crystalline substances (yield based on
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 69.2%).
(1) Melting Point: 202.degree.-206.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S 2HBr)
Calculated: C, 47.90; H, 5.57; N, 6.45
Found: C, 47.86; H, 5.78; N, 6.44
Example 17
[Preparation of
N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide hydrochloride]
N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (0.90 g, 1.84 mmol) prepared in the same manner as in Example 4 was
dissolved in methanol (10 ml). 2 M hydrochloric acid (factor =1.004) (0.92
ml) was added thereto, and the solvent was then removed by evaporation in
vacuo. Acetone was added to the residue, and the precipitated crystals
were collected by filtration. The crystals were recrystallized from
ethanol, to give
N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide hydrochloride (0.72 g) as colorless prisms (yield based on
N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 74.5%).
(1) Melting Point: 179.degree.-181.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S HCl)
Calculated: C, 59.30; H, 7.08; N, 7.98
Found: C, 59.04; H, 7.29; N, 8.00
Example 18
[Preparation of
N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide dihydrochloride]
N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide (6.20 g, 12.65 mmol) prepared in the same manner as in Example 4 was
dissolved in methanol (20 ml). 2 M Hydrochloric acid (factor 1.004) (15.00
ml) was added thereto, and the solvent was then removed by evaporation in
vacuo. Acetone was added to the residue, and the precipitated crystals
were collected by filtration. The crystals were recrystallized from
acetone, to give
N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide dihydrochloride (5.60 g) as colorless prisms (yield based on
N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide: 78.6%).
(1) Melting Point: 140.degree.-144.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S 2HCl)
Calculated: C, 55.46; H, 6.80; N, 7.46
Found: C, 55.16; H, 6.99; N, 7.49
Example 19
[Preparation of
N-(2-Hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide (904.4 mg) as a pale yellow oil (yield: 91.5%).
(1) IR vmax (neat) cm.sup.- : 3509 (OH), 3286 (NH), 1320, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.36 ClN.sub.3 O.sub.3 S) EI: m/z 493
[M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.36 ClN.sub.3 O.sub.3 S)
Calculated: 493.2164, Found: 493.2172
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-1.58 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.74-1.90 (2 H, m, SCH.sub.2 CH.sub.2), 2.07
(1 H, brs, OH), 2.34 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.38-2.52 (8 H, m,
NCH.sub.2 CH.sub.2 x2), 3.02-3.08 (2 H, m, SCH.sub.2), 3.27 (2 H, brs,
NCH.sub.2 CH.sub.2 OH), 3.75 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH),
4.22 (1 H, s, CH), 4.79 (1 H, brs, NH), 7.15-7.44 (9 H, m, ArH)
Example 20
[Preparation of N-(2-Hydroxyethyl)-6-[4-[(4-chlorophenyl
phenylmethyl]-1-piperazinyl]hexanesulfonamide dihydrochloride]
N-(2-Hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide (7.75 g, 15.69 mmol) prepared in the same manner as in Example
19 was dissolved in ethanol. A 15% HCl-methanol solution was added thereto
to make it acidic, and the solvent was removed by evaporation in vacuo.
Diethyl ether was added to the residue, and the precipitated crystals were
collected by filtration. The crystals were recrystallized from ethanol, to
give
N-(2-hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide dihydrochloride (8.10 g) as colorless prisms (yield: 91.1%).
(1) Melting Point: 136.degree.-142.degree. C.
(2) Elemental Analysis (as C.sub.25 H.sub.36 ClN.sub.3 O.sub.3 S 2HCl)
Calculated: C, 52.95; H, 6.76; N, 7.41
Found: C, 52.86; H, 6.82; N, 7.53
Example 21
[Preparation of
N-(2-Hydroxyethyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]penta
nesulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]penta
nesulfonamide (877.0 mg) as a pale yellow oil (yield: 91.4%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3282 (NH), 1318, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.24 H.sub.34 ClN.sub.3 O.sub.3 S) EI: m/z 479
[M].sup.+
(3) EI-HRMS (C.sub.24 H.sub.34 ClN.sub.3 O.sub.3 S)
Calculated: 479.2008, Found: 479.2005
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.59 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.76-1.91 (2 H, m, SCH.sub.2 CH.sub.2), 1.97 (1 H,
brs, OH), 2.36 (2 H, t, J=7.5 Hz, NCH.sub.2), 2.39-2.54 (8 H, m, NCH.sub.2
CH.sub.2 x2), 3.04-3.09 (2 H, m, SCH.sub.2), 3.27 (2 H, brs, NCH.sub.2
CH.sub.2 OH), 3.75 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH), 4.23 (1 H,
s, CH), 4.81 (1 H, brs, NH), 7.18-7.39 (9 H, m, ArH)
Example 22
[Preparation of
N-(2-Hydroxyethyl)-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dode
canesulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (610.0 mg, 2.12 mmol) and
N-(2-hydroxyethyl)-12-bromododecanesulfonamide (871.0 mg, 2.34 mmol)
obtained in Preparation Example 6 were refluxed in N-ethyldiisopropylamine
(2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and
water was added thereto. The mixture was extracted with chloroform. The
chloroform layer was washed with water, and dried over anhydrous magnesium
sulfate. Subsequently, the solvent was removed by evaporation in vacuo.
The resulting crude product was purified by column chromatography on
silica gel with chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dode
canesulfonamide (1125.0 mg) as a pale brown oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 91.7%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3286 (NH), 1321, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.31 H.sub.48 ClN.sub.3 O.sub.3 S) EI: m/z 577
[M].sup.+
(3) EI-HRMS (C.sub.31 H.sub.48 ClN.sub.3 O.sub.3 S)
Calculated: 577.3102, Found: 577.3112
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22-1.54 (18 H, m, NCH.sub.2
(CH.sub.2).sub.9 CH.sub.2 CH.sub.2 S), 1.77-1.89 (3 H, m, SCH.sub.2
CH.sub.2 OH), 2.35 (2 H, t, J=8.0 Hz, NCH.sub.2), 2.38-2.54 (8 H, m,
NCH.sub.2 CH.sub.2 x2), 3.03-3.09 (2 H, m, SCH.sub.2), 3.24-3.33 (2 H,
brs, NCH.sub.2 CH.sub.2 OH), 3.78 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2
OH), 4.23 (1 H, s, CH), 4.65 (1 H, brs, NH), 7.17-7.40 (9 H, m, ArH)
Example 23
[Preparation of
N-(3-Hydroxypropyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexa
nesulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (505.9 mg, 1.76 mmol) and
N-(3-hydroxypropyl)-6-chlorohexanesulfonamide (500.0 mg, 1.94 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(3-hydroxypropyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexa
nesulfonamide (819.3 mg) as a pale yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 91.4%).
(1) IR vahax (neat) cm.sup.-1 : 3509 (OH), 3286 (NH), 1320, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.38 ClN.sub.3 O.sub.3 S) EI: d/z 507
[M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.38 ClN.sub.3 O.sub.3 S)
Calculated: 507.2320, Found: 507.2313
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.27-1.58 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.74-1.88 (4 H, mn, SCH.sub.2 CH.sub.2,
NCH.sub.2 CH.sub.2 CH.sub.2 OH), 2.19 (1 H, brs, OH), 2.34 (2 H, t, J=7.9
Hz, NCH.sub.2), 2.38-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.99-3.05 (2 H,
SCH.sub.2), 3.25-3.31 (2 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 OH), 3.79 (2 H,
t, J=5.6 Hz, NCH.sub.2 CH.sub.2 CH.sub.2 H), 4.22 (1 H, s, CH), 4.76-4.84
(1 H, m, NH), 7.20-7.39 (9 H, m, ArH)
Example 24
[preparation of
N-(3-Hydroxypropyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pent
anesulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N-(3-hydroxypropyl)-5-chloropentanesulfonamide (487.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(3-hydroxypropyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pent
anesulfonamide (940.0 mg) as a pale yellow oil (yield: 95.1%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3281 (NH), 1318, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.36 ClN.sub.3 O.sub.3 S) EI: m/z 493
[M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.36 ClN.sub.3 O.sub.3 S)
Calculated: 493.2163, Found: 493.2161
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.39-1.60 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.72-1.90 (4 H, m, SCH.sub.2 CH.sub.2, NCH.sub.2
CH.sub.2 CH.sub.2 OH), 2.05 (1 H, brs, OH), 2.37 (2 H, t, J=7.4 Hz,
NCH.sub.2), 2.40-2.55 (8 H, m, NCH.sub.2 CH.sub.2 x2), 3.01-3.06 (2 H, m,
SCH.sub.2), 3.22-3.33 (2 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 OH), 3.78 (2 H,
t, J=5.7 Hz, NCH.sub.2 CH.sub.2 CH.sub.2 OH), 4.23 (1 H, s, CH), 4.84-4.94
(1 H, in, NH), 7.17-7.42 (9 H, m, ArH)
Example 25
[Preparation of
N-(4-Hydroxybutyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (479.8 mg, 1.67 mmol) and
N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (500.0 mg, 1.84 mmol)
prepared in Preparation Example 22 were refluxed in
N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-(4-hydroxybutyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide (828.6 mg) as a pale yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 94.9%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3286 (NH), 1321, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.27 H.sub.40 ClN.sub.3 O.sub.3 S) EI: m/z 521
[M].sup.+
(3) EI-HRMS (C.sub.27 H.sub.40 ClN.sub.3 O.sub.3 S)
Calculated: 521.2477, Found: 521.2483
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-1.56 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.59-1.72 (4 H, m, NCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 OH), 1.74-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.01 (1 H,
brs, OH), 2.34 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.38-2.53 (8 H, m, NCH.sub.2
CH.sub.2 x2), 2.98-3.03 (2 H, m, SCH.sub.2), 3.12-3.21 (2 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 OH), 3.68 (2 H, t, J=5.7 Hz, NCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 OH), 4.23 (1 H, s, CH), 4.65-4.76 (1 H, m, NH),
7.18-7.39 (9 H, m, ArH)
Example 26
[Preparation of
N-(4-Hydroxybutyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-piperazinyl]pentane
sulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol)
prepared in Preparation Example 23 were refluxed in
N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
N-(4-hydroxybutyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]penta
nesulfonamide (947.0 mg) as a pale yellow oil (yield: 93.2%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3282 (NH), 1318, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.38 ClN.sub.3 O.sub.3 S) EI: m/z 507
[M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.38 ClN.sub.3 O.sub.3 S)
Calculated: 507.2320, Found: 507.2317
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37-1.58 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.58-1.75 (4 H, m, NCH.sub.2 CH.sub.2 CH.sub.2
CH.sub.2 OH), 1.75-1.99 (3 H, m, SCH.sub.2 CH.sub.2, OH), 2.36 (2 H, t,
J=7.6 Hz, NCH.sub.2), 2.37-2.54 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.98-3.04
(2 H, m, SCH.sub.2), 3.10-3.25 (2 H, m, NCH.sub.2 CH.sub.2 CH.sub.2
CH.sub.2 OH), 3.69 (2 H, t, J=5.7 Hz, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2
OH), 4.23 (1 H, s, CH), 4.68-4.80 (1 H, m, NH), 7.17-7.42 (9 H, m, ArH)
Example 27
[Preparation of
N-(2-Hydroxyethyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesu
lfonamide]
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesu
lfonamide (915.2 mg) as a pale yellow oil (92.3%).
(1) IR vmax (neat) cm.sup.-1 : 3502 (OH), 3287 (NH), 1320, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.35 F.sub.2 N.sub.3 O.sub.3 S) EI: m/z
495 [M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.35 F.sub.2 N.sub.3 O.sub.3 S)
Calculated: 495.2365, Found: 495.2362
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-1.57 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.77-1.90 (2 H, m, SCH.sub.2 CH.sub.2), 2.07
(1 H, brs, OH), 2.34 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.37-2.53 (8 H, m,
NCH.sub.2 CH.sub.2 x2), 3.02-3.08 (2 H, m, SCH.sub.2), 3.27 (2 H, brs,
NCH.sub.2 CH.sub.2 OH), 3.75 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH),
4.23 (1 H, s, CH), 4.78 (1 H, brs, NH), 6.95-7.02 (4 H, m, ArH), 7.32-7.37
(4 H, m, ArH)
Example 28
[Preparation of
N-(2-Hydroxvethyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentanes
ulfonamide]
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-
piperaziny]pentanesulfonamide (905.6 mg) as a pale yellow oil (94.0%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3286 (NH), 1321, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.24 H.sub.33 F.sub.2 N.sub.3 O.sub.3 S) EI:
m/z 481 [M].sup.+( 3) EI-HRMS (C.sub.24 H.sub.33 F.sub.2 N.sub.2 O.sub.3
S)
Calculated: 481.2209, Found: 481.2212
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.57 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.79-1.91 (2 H, m, SCH.sub.2 CH.sub.2), 2.10-2.30 (1
H, br, OH), 2.36 (2 H, t, J=7.5 Hz, NCH.sub.2), 2.40-2.53 (8 H, in,
NCH.sub.2 CH.sub.2 x2), 3.04-3.09 (2 H, in, SCH.sub.2), 3.27 (2 H, brs,
NCH.sub.2 CH.sub.2 OH), 3.75 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH),
4.23 (1 H, s, CH), 4.84 (1 H, brs, NH), 6.95-7.02 (4 H, m, ArH), 7.33-7.38
(4 H, in, ArH)
Example 29
[Preparation of
N-(3-Hydroxypropyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanes
ulfonamide]
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and
N-(3-hydroxypropyl)-6-chlorohexanesulfonamide (515.6 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuc, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(3-hydroxypropyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanes
ulfonamide (976.6 mg) as a pale yellow oil (95.8%).
(1) IR vmax (neat) cm.sup.-1 : 3502 (OH), 3286 (NH), 1320, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.37 F.sub.2 N.sub.3 O.sub.3 S) EI: m/z
509 [M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.37 F.sub.2 N.sub.3 O.sub.3 S)
Calculated: 509.2522, Found: 509.2522
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-1.58 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.75-1.88 (4 H, m, SCH.sub.2 CH.sub.2,
NCH.sub.2 CH.sub.2 CH.sub.2 OH), 2.00-2.30 (1 H, br, OH), 2.34 (2 H, t,
J=7.9 Hz, NCH.sub.2), 2.37-2.52 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.99-3.05
(2 H, m, SCH.sub.2), 3.25-3.31 (2 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 OH),
3.79 (2 H, t, J=5.7 Hz, NCH.sub.2 CH.sub.2 CH.sub.2 OH), 4.23 (1 H, s,
CH), 4.73-4.82 (1 H, m, NH), 6.95-7.02 (4 H, m, ArH), 7.33-7.38 (4 H, m,
ArH)
Example 30
[Preparation of
N-(3-Hydroxypropyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentane
sulfonamide]-1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg,
2.00 mmol) and N-(3-hydroxypropyl)-5-chloropentanesulfonamide (487.5 mg,
2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours.
The reaction mixture was concentrated in vacuo, and water was added
thereto. The mixture was extracted with chloroform. The chloroform layer
was washed with water, and dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by evaporation in vacuo. The
resulting crude product was purified by column chromatography on silica
gel with chloroform-methanol (20:1), to give
N-(3-hydroxypropyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentane
sulfonamide (913.0 mg) as a pale yellow oil (92.1%).
(1) IR vmax (neat) cm.sup.-1 : 3502 (OH), 3287 (NH), 1318, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.35 F.sub.2 N.sub.3 O.sub.3 S) EI: m/z
495 [M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.35 F.sub.2 N.sub.3 O.sub.3 S)
Calculated: 495.2365, Found: 495.2364
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.41-1.58 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.75-1.89 (4 H, m, SCH.sub.2 CH.sub.2, NCH.sub.2
CH.sub.2 CH.sub.2 OH), 2.36 (2 H, t, J=7.3 Hz, NCH.sub.2), 2.38-2.53 (8 H,
m, NCH.sub.2 CH.sub.2 x2), 3.01-3.05 (2 H, m, SCH.sub.2), 3.25-3.31 (2 H,
m, NCH.sub.2 CH.sub.2 CH.sub.2 OH), 3.79 (2 H, t, J=5.6 Hz, NCH.sub.2
CH.sub.2 CH.sub.2 OH), 4.23 (1 H, s, CH), 4.81-4.89 (1 H, m, NH),
6.95-7.02 (4 H, m, ArH), 7.33-7.38 (4 H, m, ArH)
Example 31
[Preparation of
N-(4-Hydroxybutyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesu
lfonamide]
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and
N-(4-hydroxybutyl)-6-chlorohexanesulfonamide (543.6 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(4-hydroxybutyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesu
lfonamide (1001.2 mg) as a pale yellow oil (95.6%).
(1) IR vmax (neat) cm.sup.-1 : 3502 (OH), 3286 (NH), 1321, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.27 H.sub.39 F.sub.2 N.sub.3 O.sub.3 S) EI: m/z
523 [M].sup.+
(3) EI-HRMS (C.sub.27 H.sub.39 F.sub.2 N.sub.3 O.sub.3 S)
Calculated: 523.2678, Found: 523.2679
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-1.57 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.60-1.75 (4 H, m, NCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 OH), 1.75-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.07 (1 H,
br, OH), 2.33 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.37-2.53 (8 H, m, NCH.sub.2
CH.sub.2 x2), 2.98-3.03 (2 H, m, SCH.sub.2), 3.12-3.21 (2 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2 OH), 3.68 (2 H, t, J=5.7 Hz, NCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 OH), 4.23 (1 H, s, CH), 4.68-4.76 (1 H, m, NH),
6.95-7.02 (4 H, m, ArH), 7.32-7.38 (4 H, m, ArH)
Example 32
[Preparation of
N-(4-Hydroxybutyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentanes
ulfonamide]
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and
N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(4-hydroxybutyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentanes
ulfonamide (934.3 mg) as a pale yellow oil (91.7%).
(1) IR vmax (neat) cm.sup.-1 : 3502 (OH), 3286 (NH), 1320, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.37 F.sub.2 N.sub.3 O.sub.3 S) EI: m/z
509 [M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.37 F.sub.2 N.sub.3 O.sub.3 S)
Calculated: 509.2522, Found: 509.2520
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.57 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.60-1.75 (4 H, m, NCH.sub.2 CH.sub.2 CH.sub.2
CH.sub.2 OH), 1.77-1.89 (2 H, m, SCH.sub.2 CH.sub.2), 1.92 (1 H, brs, OH),
2.35 (2 H, t, J=7.6 Hz, NCH.sub.2), 2.37-2.52 (8 H, m, NCH.sub.2 CH.sub.2
x2), 2.99-3.04 (2 H, m, SCH.sub.2), 3.13-3.21 (2 H, m, NCH.sub.2 CH.sub.2
CH.sub.2 CH.sub.2 OH), 3.69 (2 H, t, J=5.8 Hz, NCH.sub.2 CH.sub.2 CH.sub.2
CH.sub.2 OH), 4.23 (1 H, s, CH), 4.68-4.77 (1 H, m, NH), 6.95-7.02 (4 H,
m, ArH), 7.32-7.38 (4 H, m, ArH)
Example 33
[Preparation of
N-(2-Hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-Piperazinyl]hexanesu
lfonamide]
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesu
lfonamide (975.0 mg) as a pale brown oil (92.2%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3282 (NH), 1321, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.35 C.sub.12 N.sub.3 O.sub.3 S) EI:
m/z 527 [M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.35 Cl.sub.2 N.sub.3 O.sub.3 S)
Calculated: 527.1774, Found: 527.1771
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.27-1.56 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.65-2.00 (3 H, mn, SCH.sub.2 CH.sub.2, OH),
2.34 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.37-2.55 (8 H, m, NCH.sub.2 CH.sub.2
x2), 3.03-3.08 (2 H, m, SCH.sub.2), 3.22-3.33 (2 H, m, NCH.sub.2 CH.sub.2
OH), 3.76 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH), 4.21 (1 H, s, CH),
4.74 (1 H, brs, NH), 7.22-7.38 (8 H, m, ArH)
Example 34
[Ppreparation of
N-(2-Hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanes
ulfonamide]
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and
N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-(2-hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanes
ulfonamide (1003.0 mg) as a pale brown oil (97.5%).
(1) IR vmax (neat) cm.sup.-1 : 3509 (OH), 3282 (NH), 1320, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.24 H.sub.33 Cl.sub.2 N.sub.3 O.sub.3 S) EI:
m/z 513 [M].sup.+
(3) EI-HRMS (C.sub.24 H.sub.33 Cl.sub.2 N.sub.3 O.sub.3 S)
Calculated: 513.1618, Found: 513.1604
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.39-1.58 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.64-2.30 (3 H, m, SCH.sub.2 CH.sub.2, OH), 2.34 (2 H,
t, J=7.5 Hz, NCH.sub.2), 2.38-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2),
3.04-3.09 (2 H, m, SCH.sub.2), 3.23-3.32 (2 H, m, NCH.sub.2 CH.sub.2 OH),
3.76 (2 H, t, J=5.2 Hz, NCH.sub.2 CH.sub.2 OH), 4.21 (1 H, s, CH), 4.79 (1
H, brs, NH), 7.25-7.34 (8 H, m, ArH)
Example 35
[Preparation of
N-Cyclopropyl-10-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]decanesul
fonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (525.0 mg, 1.83 mmol) and
N-cyclopropyl-10-bromodecanesulfonamide (685.0 mg, 2.01 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with chloroform, to
give
N-cyclopropyl-10-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]decanesul
fonamide (964.0 mg) as a pale brown oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.5%).
(1) IR vmax (neat) cm.sup.-1 : 3275 (NH), 1318, 1146 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.30 H.sub.44 ClN.sub.3 O.sub.2 S) EI: m/z 545
[M].sup.+
(3) EI-HRMS (C.sub.30 H.sub.44 ClN.sub.3 O.sub.2 S)
Calculated: 545.2840, Found: 545.2837
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.67-0.83 (4 H, m, CHCH.sub.2
CH.sub.2), 1.23-1.57 (14 H, m, NCH.sub.2 (CH.sub.2).sub.7 CH.sub.2
CH.sub.2 S), 1.72-1.91 (2 H, m, SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=8.2
Hz, NCH.sub.2), 2.39-2.55 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.56-2.63 (1 H,
m, CHCH.sub.2 CH.sub.2), 3.05-3.10 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH),
4.65 (1 H, brs, NH), 7.17-7.48 (9 H, m, ArH)
Example 36
[Preparation of
N-Cyclopropyl-11-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]undecanes
ulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (642.7 mg, 2.24 mmol) and
N-cyclopropyl-11-bromoundecanesulfonamide (873.0 mg, 2.46 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with chloroform, to
give
N-cyclopropyl-11-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]undecanes
ulfonamide (1210.0 mg) as a pale yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 96.4%).
(1) IR vmax (neat) cm.sup.-1 : 3274 (NH), 1318, 1147 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.31 H.sub.46 ClN.sub.3 O.sub.2 S) EI: m/z 559
[M].sup.+
(3) EI-HRMS (C.sub.31 H.sub.46 ClN.sub.3 O.sub.2 S)
Calculated: 559.2997, Found: 559.2990
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.68-0.77 (4 H, m, CHCH.sub.2
CH.sub.2), 1.23-1.53 (16 H, m, NCH.sub.2 (CH.sub.2).sub.8 CH.sub.2
CH.sub.2 S), 1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.33 (2 H, t, J=7.9
Hz, NCH.sub.2), 2.37-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.55-2.63 (1 H,
m, CHCH.sub.2 CH.sub.2), 3.05-3.11 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH),
4.60 (1 H, brs, NH), 7.16-7.41 (9 H, m, ArH)
Example 37
[Preparation of
N-Cyclopropyl-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dodecanes
ulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (629.0 mg, 2.20 mmol) and
N-cyclopropyl-12-bromododecanesulfonamide (891.0 mg, 2.42 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with chloroform, to
give
N-cyclopropyl-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dodecanes
ulfonamide (1243.0 mg) as a pale brown oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 98.4%).
(1) IR vmax (neat) cm.sup.-1 : 3274 (NH), 1318, 1146 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.32 H.sub.48 ClN.sub.3 O.sub.2 S) EI: m/z 573
[M].sup.+
(3) EI-HRMS (C.sub.32 H.sub.48 ClN.sub.3 O.sub.2 S)
Calculated: 573.3153, Found: 573.3152
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.67-0.78 (4 H, m, CHCH.sub.2
CH.sub.2), 1.22-1.53 (18 H, m, NCH.sub.2 (CH.sub.2),CH.sub.2 CH.sub.2 S),
1.76-1.87 (2 H, m, SCH.sub.2 CH.sub.2), 2.33 (2 H, t, J=8.0 Hz,
NCH.sub.2), 2.37-2.54 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.54-2.63 (1 H, m,
CHCH.sub.2 CH.sub.2), 3.05-3.11 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH),
4.63 (1 H, brs, NH), 7.16-7.40 (9 H, m, ArH)
Example 38
[Preparation of
N,N-Dimethyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfo
namide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N,N-dimethyl-6-chlorohexanesulfonamide (455.5 mg, 2.00 mmol) were refluxed
in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (50:1), to
give
N,N-dimethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfon
amide (880.0 mg) as a pale brown oil (yield: 92.1%).
(1) IR vmax (neat) cm.sup.-1 : 1329, 1139 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.25 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 477
[M].sup.+
(3) EI-HRMS (C.sub.25 H.sub.36 ClN.sub.3 O.sub.2 s)
Calculated: 477.2215, Found: 477.2219
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.27-1.55 (6 H, m, NCH.sub.2
CH.sub.2 CH.sub.2 CH.sub.2), 1.76-1.88 (2 H, m, SCH.sub.2 CH.sub.2), 2.34
(2 H, t, J=7.9 Hz, NCH.sub.2), 2.38-2.54 (8 H, m, NCH.sub.2 CH.sub.2 x2),
2.88 (6 H, s, CH.sub.3 x2), 2.88-2.94 (2 H, m, SCH.sub.2), 4.22 (1 H, s,
CH), 7.16-7.40 (9 H, m, ArH)
Example 39
[Preparation of
N,N-Dimethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulf
onamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N,N-dimethyl-5-chloropentanesulfonamide (470.2 mg, 2.20 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (50:1), to give
N,N-dimethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulf
onamide (857.7 mg) as a yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.4%).
(1) IR vmax (neat) cm.sup.-1 : 1336, 1148 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.24 H.sub.34 ClN.sub.3 O.sub.2 S) EI: m/z 463
[M].sup.+
(3) EI-HRMS (C.sub.24 H.sub.34 ClN.sub.3 O.sub.2 S)
Calculated: 463.2059, Found: 463.2067
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.58 (4 H, m, NCH.sub.2
CH.sub.2 CH.sub.2), 1.77-1.90 (2 H, m, SCH.sub.2 CH.sub.2), 2.35 (2 H, t,
J=7.7 Hz, NCH.sub.2), 2.38-2.53 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.88 (6
H, s, CH.sub.3 x2), 2.89-2.94 (2 H, m, SCH.sub.2), 4.22 (1 H, s, CH),
7.20-7.40 (9 H, m, ArH)
Example 40
[Preparation of
N,N-Diethyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfon
amide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N,N-diethyl-6-chlorohexanesulfonamide (511.6 mg, 2.00 mmol) were refluxed
in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (50:1), to
give
N,N-diethyl-6-[4-[(4-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfona
mide (951.0 mg) as a pale brown oil (yield: 94.0%).
(1) IR vmax (neat) cm.sup.-1 : 1336, 1147 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.27 H.sub.40 ClN.sub.3 O.sub.2 S) EI: m/z 505
[M].sup.+
(3) EI-HRMS (C.sub.27 H.sub.40 ClN.sub.3 O.sub.2 S)
Calculated: 505.2527, Found: 505.2517
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21 (6 H, t, J=7.1 Hz, CH.sub.2
CH.sub.3 x2), 1.27-1.54 (6 H, m, NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2),
1.73-1.86 (2 H, m, SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.8 Hz,
NCH.sub.2), 2.37-2.52 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.88-2.94 (2 H, m,
SCH.sub.2), 3.30 (4 H, q, J=7.1 Hz, CH.sub.2 CH.sub.3 x2), 4.22 (1 H, s,
CH), 7.16-7.40 (9 H, m, ArH)
Example 41
[Preparation of
N,N-Diethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfo
namide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N,N-diethyl-5-chloropentanesulfonamide (531.9 mg, 2.20 mmol) were refluxed
in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (50:1), to
give
N,N-diethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfo
namide (905.2 mg) as a yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.0%).
(1) IR vmax (neat) cm.sup.-1 : 1329, 1140 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.26 H.sub.38 ClN.sub.3 O.sub.2 S) EI: m/z 491
[M].sup.+
(3) EI-HRMS (C.sub.26 H.sub.38 ClN.sub.3 O.sub.2 S)
Calculated: 491.2371, Found: 491.2364
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21 (6 H, t, J=7.1 Hz, CH.sub.2
CH.sub.3 x2), 1.38-1.57 (4 H, m, NCH.sub.2 CH.sub.2 CH.sub.2), 1.76-1.88
(2 H, m, SCH.sub.2 CH.sub.2), 2.35 (2 H, t, J=7.7 Hz, NCH.sub.2),
2.37-2.52 (8 H, m, NCH.sub.2 CH.sub.2 x2), 2.89-2.94 (2 H, m, SCH.sub.2),
3.29 (4 H, q, J=7.1 Hz, CH.sub.2 CH.sub.3 x2), 4.22 (1 H, S, CH),
7.17-7.40 (9 H, m, ArH)
Example 42
[Preparation of
N-n-Butyl-N-methyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide]
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and
N-n-butyl-N-methyl-6-chlorohexanesulfonamide (539.7 mg, 2.00 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (50:1), to give
N-n-butyl-N-methyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexan
esulfonamide (951.0 mg) as a pale brown oil (yield: 91.4%).
(1) IR vmax (neat) cm.sup.-1 : 1334, 1143 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.28 H.sub.42 ClN.sub.3 O.sub.2 S) EI: m/z 519
[M].sup.+
(3) EI-HRMS (C.sub.28 H.sub.42 ClN.sub.3 O.sub.2 S)
Calculated: 519.2684, Found: 519.2682
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.96 (3 H, t, J=7.3 Hz, CH.sub.2
CH.sub.3), 1.27-1.63 (10 H, m, NCH.sub.2 (CH.sub.2).sub.3 CH.sub.2
CH.sub.2 S, NCH.sub.2 (CH.sub.2).sub.2 CH.sub.3), 1.74-1.86 (2 H, m,
SCH.sub.2 CH.sub.2), 2.34 (2 H, t, J=7.9 Hz, NCH.sub.2), 2.37-2.52 (8 H,
m, NCH.sub.2 CH.sub.2 x2), 2.86 (3 H, s, NCH.sub.3), 2.88-2.94 (2 H, m,
SCH.sub.2), 3.16 (2 H, t, J=7.4 Hz, NCH.sub.2 (CH.sub.2).sub.2 CH.sub.3),
4.22 (1 H, s, CH), 7.17-7.40 (9 H, m, ArH)
Example 43
[Preparation of
N-n-Butyl-N-methyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]penta
nesulfonamide]
1-[(4-Chlorophenyl)phenylmethyl-3-piperazine (624.0 mg, 2.17 mmol) and
N-n-butyl-N-methyl-5-chloropentanesulfonamide (612.0 mg, 2.39 mmol) were
refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction
mixture was concentrated in vacuo, and water was added thereto. The
mixture was extracted with chloroform. The chloroform layer was washed
with water, and dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with chloroform, to
give
N-n-butyl-N-methyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]penta
nesulfonamide (1029.0 mg) as a yellow oil (yield based on
1-[(4-chlorophenyl)phenylmethyl]piperazine: 93.6%).
(1) IR vmax (neat) cm.sup.-1 : 1333, 1144 (SO.sub.2)
(2) Mass Spectroscopy (C.sub.27 H.sub.40 C1N.sub.3 O.sub.2 S) EI: m/z 505
[M].sup.+
(3) EI-HRMS (C.sub.27 H.sub.40 ClN.sub.3 O.sub.2 S)
Calculated: 505.2527, Found: 505.2522
(4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.96 (3 H, t, J=7.3 Hz, CH.sub.2
CH.sub.3), 1.30-1.64 (8 H, m, NCH.sub.2 (CH.sub.2).sub.2 CH.sub.2 CH.sub.2
S, NCH.sub.2 (CH.sub.2).sub.2 CH.sub.3), 1.77-1.88 (2 H, m, SCH.sub.2
CH.sub.2), 2.35 (2 H, t, J=7.7 Hz, NCH.sub.2), 2.38-2.53 (8 H, m,
NCH.sub.2 CH.sub.2 x2), 2.86 (3 H, s, NCH.sub.3), 2.88-2.94 (2 H, m,
SCH.sub.2), 3.16 (2 H, t, J=7.4 Hz, NCH.sub.2 (CH.sub.2).sub.2 CH.sub.3),
4.22 (1 H, s, CH), 7.17-7.40 (9 H, m, ArH)
Example 44
[Preparation of
(+)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide]
(+)-1-[(3-Chlorophenyl)phenylmethyl]piperazine (2.27 g, 7.90 mmol) prepared
in the same manner as in Preparation Example 18 and
N-cyclopropyl-6-chlorohexanesulfonamide (2.08 g, 8.69 mmol) were refluxed
in N-ethyldiisopropylamine (10 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1)],
to give
(+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide (3.35 g) as a pale yellow oil (yield based on
(+)-1-[(3-chlorophenyl)phenylmethyl]piperazine: 86.4%).
(1) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(2) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2214, Found: 489.2208
(3) [.alpha.].sub.D.sup.26 +11.1.degree. (c =4.50, methanol)
In order to determine the optical purity of the resulting
(+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide, HPLC analysis was carried out. Its analytical conditions are
as follows.
[HPLC Analytical Conditions]
Column: ULTRON ES-OVM, 4.6 mm.times.150 mm (5 .mu.m)
Mobile Phase: ethanol:phosphate buffer (pH 6.0)
=3:7
Flow Rate: 0.9 ml/min.
Detection: at UV 254 nm
Retention Time
[N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide (racemate)]:
9.2 min. [50%, (+)-form]
13.1 min. [50%, (-)-form]
Subject: 9.5 min. (98.8%), 14.1 min. (1.2%)
From the above results, it was found that the optical purity of the
(+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide obtained in Example 44 was 97.6% ee.
Example 45
[Preparation of
(+)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide dihydrochloride]
(+)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanes
ulfonamide (3.26 g, 6.65 mmol) prepared in the same manner as in Example 15
was formed into a hydrochloride salt in a 15% HCl-methanol solution. The
resulting hydrochloride salt was recrystallized from ethanol, to give
(+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide dihydrochloride (3.10 g) as colorless prisms (yield: 82.8%).
(1) Melting Point: 162.degree.-164.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S 2HCl)
Calculated: C, 55.46; H, 6.80; N, 7.46
Found: C, 55.42; H, 6.52; N, 7.44
(3) [.alpha.].sub.D.sup.26 +5.1.degree. (c =1.0, methanol)
Example 46
[Preparation of
(-)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide]
(-)-1-[(3-Chlorophenyl)phenylmethyl]piperazine (2.60 g, 9.06 mmol) prepared
in the same manner as in Preparation Example 21 and
N-cyclopropyl-6-chlorohexanesulfonamide (2.40 g, 10.00 mmol) were refluxed
in N-ethyldiisopropylamine (13 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
(-)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide (3.78 g) as a pale yellow oil (yield based on
(-)-1-[(3-chlorophenyl)phenylmethyl]piperazine: 86.0%).
(1) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(2) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2214, Found: 489.2215
(3) [.alpha.].sub.D.sup.26 -10.6.degree. (c =5.60, methanol)
In order to determine the optical purity of the resulting
(-)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide, HPLC analysis was carried out in accordance with the process
in Example 44. As a result, it was found that the optical purity of the
(-)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide was 97.6% ee.
Example 47
[Preparation of
(-)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide dihydrochloride]
(-)-N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanes
ulfonamide (3.69 g, 7.53 mmol) prepared in the same manner as in Example 15
was formed into a hydrochloride salt in a 15% HCl-methanol solution. The
resulting hydrochloride salt was recrystallized from ethanol, to give
(-)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide dihydrochloride (3.26 g) as colorless prisms (yield: 76.9%).
(1) Melting Point: 162.degree.-165.degree. C.
(2) Elemental Analysis (as C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S2HCl)
Calculated: C, 55.46; H, 6.80; N, 7.46
Found: C, 55.25; H, 6.65; N, 7.45
(3) [.alpha.].sub.D.sup.26 -5.1.degree. (c =1.0, methanol)
Example 48
[Preparation of
(+)-N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide]
(+)-1-[(4-Chlorophenyl)phenylmethyl]piperazine (1.35 g, 4.71 mmol) [optical
purity 99.0%, [.alpha.].sub.D.sup.27 +14.9.degree. (c =1.00, methanol)]
obtained in accordance with the process described in J. Chem. Soc.,
1958-1960 (1939) or Japanese Patent Laid-Open No. 2816/1995 and
N-cyclopropyl-6-chlorohexanesulfonamide (1.24 g, 5.18 mmol) were refluxed
in N-ethyldiisopropylamine (10 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
(+)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide (2.10 g) as a pale yellow oil (yield based on
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine: 91.3%).
(1) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(2) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2214, Found: 489.2216
(3) [.alpha.].sub.D.sup.27 +5.3.degree. (c =5.40, methanol) In order to
determine the optical purity of the resulting
(+)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide, HPLC analysis was carried out. Its analytical conditions are
as follows.
[HPLC Analytical Conditions]
Column: ULTRON ES-OVM, 4.6 mm.times.150 mm (5 .mu.m)
Mobile Phase: acetonitrile:acetate buffer (pH 5.1)=13:87
Flow Rate: 1.5 ml/min.
Detection: at UV 254 nm
Retention Time
[N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesul
fonamide (racemate)]:
9.4 min. [50%, (+)-form]
15.7 min. [50%, (-)-form]
Subject: 9.5 min. (99.5%), 15.7 min. (0.5%)
From the above results, it was found that the optical purity of the
(+)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide obtained in Example 48 was 99.0% ee.
Example 49
[Preparation of
(-)-N-Cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide]
(-)-1-[(4-Chlorophenyl)phenylmethyl]piperazine (1.20 g, 4.18 mmol) [optical
purity 98.4%, [.alpha.].sub.D.sup.27 -14.2.degree. (c =1.153, methanol)]
obtained in accordance with the process described in J. Chem. Soc.,
1958-1960 (1939) or Japanese Patent Laid-Open No. 2816/1995 and
N-cyclopropyl-6-chlorohexanesulfonamide (1.10 g, 4.59 mmol) were refluxed
in N-ethyldiisopropylamine (10 ml) for 4 hours. The reaction mixture was
concentrated in vacuo, and water was added thereto. The mixture was
extracted with chloroform. The chloroform layer was washed with water, and
dried over anhydrous magnesium sulfate. Subsequently, the solvent was
removed by evaporation in vacuo. The resulting crude product was purified
by column chromatography on silica gel with chloroform-methanol (20:1), to
give
(-)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide (1.64 g) as a pale yellow oil (yield based on
(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine: 80.0%).
(1) Mass Spectroscopy (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S) EI: m/z 489
[M].sup.+
(2) EI-HRMS (C.sub.26 H.sub.36 ClN.sub.3 O.sub.2 S)
Calculated: 489.2214, Found: 489.2216
(3) [.alpha.].sub.D.sup.27 -5.1.degree. (c =4.50, methanol)
In order to determine the optical purity of the resulting
(-)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide, HPLC analysis was carried out in accordance with the process
in Example 48. As a result, it was found that the optical purity of the
(-)-N-cyclopropyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexane
sulfonamide was 98.2% ee.
Comparative Example 1
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed
in toluene (15 ml) for 4 hours in the presence of triethylamine (211 mg,
2.09 mmol). The reaction mixture was washed with water, and the organic
layer was dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (84.1 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 9.0%).
The resulting
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide had physical properties similar to those of
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide obtained in Example 1.
Comparative Example 2
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and
N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed
in toluene (15 ml) in the presence of triethylamine (211 mg, 2.09 mmol)
for 48 hours. The reaction mixture was washed with water, and the organic
layer was dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (482.7 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 52.0%).
The resulting
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide had physical properties similar to those of
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide obtained in Example 1.
Comparative Example 3
[Preparation of
N-Cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide]
1-[(3-Chlorophenyl)phenylmethyl]piperazine (435.2 mg, 1.52 mmol) and
N-cyclopropyl-6-bromohexanesulfonamide (474.5 mg, 1.67 mmol) were refluxed
in toluene (15 ml) in the presence of triethylamine (169 mg, 1.67 mmol)
for 42 hours. The reaction mixture was washed with water, and the organic
layer was dried over anhydrous magnesium sulfate. Subsequently, the
solvent was removed by evaporation in vacuo. The resulting crude product
was purified by column chromatography on silica gel with
chloroform-methanol (20:1), to give
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide (499.0 mg) as an oil (yield based on
1-[(3-chlorophenyl)phenylmethyl]piperazine: 67.1%).
The resulting
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide had physical properties similar to those of
N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulf
onamide obtained in Example 1.
It is clear from the above results that the piperizinesulfonamide
derivatives and salts thereof can be industrially advantageously prepared
in a short period of time and at high yield according to the processes of
Examples.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using
simple routine experimentation, many equivalents to the specific
embodiments of the invention described in the present specification. Such
equivalents are intended to be encompassed in the scope of the present
invention as described in the following claims.
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